Methods of treatment of anorectal and genital disorders

ABSTRACT

A topical anorectal or genital composition includes at least one film forming ingredient; at least one surfactant; at least one non-polar volatile siloxane solvent; at least 15% (w/w) water; and a therapeutically effective concentration of at least one pharmaceutical agent, wherein the composition is sufficiently designed to dry within 60 seconds after application to the anorectal or genital surface to form a dried composition, and wherein the dried composition forms: a flexible film, wherein the flexible film closely follows irregularities of the body surface as well as movement of the body surface, and (ii) a durable film, wherein the durable film does not crack or flake off and remains intact for more than 12 hours giving release of the pharmaceutical agent for an extended period of time.

RELATED APPLICATION

This application is a divisional of U.S. application Ser. No.14/203,329, filed Mar. 10, 2014, which claims the benefit of andpriority to U.S. Provisional Application No. 61/775,598, filed Mar. 10,2013, which is incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

Anal and genital disorders are widespread and include a number ofdifferent conditions such as anal warts, genital warts, hemorrhoids,anal fissures, anal cracks, anal fistulas, anal abscesses, analpruritus, herpes, other local genital and anorectal lesions. Topicaldisorders include common warts. Currently, there are a number oftopically applied formulations for the treatment of the aboveconditions, including ointments, creams, gels, lotions, jellies andpastes, foams, sprays and medicated pads.

SUMMARY OF THE INVENTION

Topical compositions and methods of treatment of anorectal and genitaldisorders are disclosed herein.

According to aspects illustrated herein, there is provided a topicalanorectal or genital composition that includes at least one flexiblefilm forming agent; at least one surfactant; at least one non-polarvolatile siloxane solvent; at least 15% (w/w) water; and atherapeutically effective concentration of at least one pharmaceuticalagent, wherein the composition is sufficiently designed to dry within 60seconds after application to an anorectal or genital surface to form adried composition, and wherein the dried composition forms: a flexiblefilm, wherein the flexible film closely follows irregularities of thesurface as well as movement of the surface, and (ii) a durable film,wherein the durable film does not crack or flake off and remains intactfor more than 12 hours giving release of the pharmaceutical agent for anextended period of time.

According to aspects illustrated herein, there is provided a topicalcomposition that includes from about 10.0% (w/w) to about 30.0% (w/w) oftrimethylsiloxysilicate; from about 1.0% (w/w) to about 5.0% (w/w) of atleast one surfactant selected from the group consisting of sodium laurylsulfate, alkyl- and alkoxy-dimethicone copolyol, polysorbate and acombination thereof; from about 30.0% (w/w) to about 75.0% (w/w) of anon-polar volatile siloxane solvent; and from about 0.005% (w/w) toabout 25.0% (w/w) of a pharmaceutical agent selected from the groupconsisting of pramoxine, phenylephrine, hydrocortisone, salicylic acid,nitroglycerine, sildenafil, procaine, lidocaine, tetracaine, dibucaine,prilocaine, phenacaine, benzyl alcohol, benzocaine, diperodon,dyclonine, dimethisoquin, epinephrine, tetrahydrozoline hydrochloride,an amphetamine, an antihistamine, methylphenidate, mephedrone,oxymetazoline, pseudoephedrine, psilocybin, ephedrine sulphateimiquimod, podophyllin, podophylotoxin, trichloroacetic acid,bichloroacetic acid, formic acid, fluorouracil, sinecatechins, plantextracts, or their salts and combinations thereof, wherein thecomposition is sufficiently designed to dry within 60 seconds afterapplication to a genital or anorectal surface to form a driedcomposition, and wherein the dried composition forms: a flexible film,wherein the flexible film closely follows irregularities of the surfaceas well as movement of the surface, and (ii) a durable film, wherein thedurable film does not crack or flake off and remains intact for morethan 12 hours giving release of the pharmaceutical agent for an extendedperiod of time.

According to some embodiments, if the anorectal or genital disorder isanal or genital warts, the pharmaceutical agent to be administered isselected from the group consisting of an immunomodulator, a cytotoxin,an anti-inflammatory agent, and combinations thereof.

Genital warts comprise vaginal warts and penile warts.

According to additional embodiments, the composition for use in treatingor preventing anal or genital warts comprises about 4.0% (w/w) to about5.0% (w/w) imiquimod. Alternatively, the composition comprises about0.5% (w/w) podophyllotoxin. Further alternatively, the compositioncomprises about 1.0% (w/w) to about 20% (w/w) salicylic acid, about 0.1%(w/w) to about 10% (w/w) 5-fluorouracil or a combination thereof.

According to some embodiments, if the topical disorder is herpes, thepharmaceutical agent is an antiviral selected from the group consistingof acyclovir, penciclovir, famciclovir, docosanol and combinationsthereof.

Herpes is a viral affliction, usually transmitted through sexualcontact.

Available topical regimens include penciclovir cream, 1% (applied every2 hours during waking hours for 4 days) and acyclovir cream, 5% (applied5 times a day for 4 days). Docosanol, a saturated fatty alcohol, is asafe and effective topical application that has been approved by theUnited States Food and Drug Administration for herpes labialis in adultswith properly functioning immune systems.

All the above treatments are applied topically several times a day whichis a disadvantage. Formulating the above pharmaceuticals agents in thecompositions of the present invention may lead to improved and speedierhealing as well as better patient compliance.

According to some embodiments, if the genital disorder is genital warts,the pharmaceutical agent is selected from the group consisting of animmunomodulator, a cytotoxin, an anti-inflammatory agent, andcombinations thereof.

According to additional embodiments, the composition for use in treatingor preventing anal or genital warts comprises about 4.0% (w/w) to about5% (w/w) imiquimod. Alternatively, the composition comprises about 0.5%(w/w) podophyllotoxin. Further alternatively, the composition comprisesabout 1.0% (w/w) to about 20% (w/w) salicylic acid, about 0.1% (w/w) toabout 10% (w/w) 5-fluorouracil or a combination thereof.

According to a further aspect, the present invention provides a methodof preventing or treating an anorectal or genital disorder comprisingapplying the composition of the present invention to an anorectal or agenital region of a subject in need of such treatment, therebypreventing or treating the anorectal or genital disorder.

According to aspects illustrated herein, there are provided topicalcompositions that include at least one flexible film forming ingredient,at least one surfactant, at least one non-polar volatile siloxanesolvent, and a therapeutically effective concentration of at least onepharmaceutical agent, wherein the composition is sufficiently designedto dry within 60 seconds after application to a genital or anorectalsurface to form a dried composition, and wherein the dried compositionforms: (i) a flexible film, wherein the flexible film closely followsirregularities of the surface as well as movement of the surface, and(ii) a durable film, wherein the durable film does not crack or flakeoff and remains intact for more than 12 hours giving release of thepharmaceutical agent for an extended period of time.

According to aspects illustrated herein, there is provided a method ofpreventing or treating an anorectal or a genital disorder that includestopically applying, once daily to a genital or anorectal surface of asubject in need of such treatment, a therapeutically effective amount ofa topical composition of the present invention.

According to aspects illustrated herein, there is provided a method ofpreventing or treating an anorectal or a genital disorder that includestopically applying, once every other day or twice weekly to a genital oranorectal surface of a subject in need of such treatment, atherapeutically effective concentration of a topical composition of thepresent invention.

The above methods of preventing or treating an anorectal or genitaldisorder achieve a similar or better therapeutic effect thancommercially available compositions comprising the same activeingredient(s) in the same concentrations wherein applied several timesdaily.

The topical disorders treated with the compositions of the presentinvention include, but are not limited to, hemorrhoids, anal fissures,anal cracks, anal fistulas, anal abscesses, anal pruritus, other localanorectal lesions, common warts, genital warts, anal warts, and herpes.

BRIEF DESCRIPTION OF THE DRAWINGS

The presently disclosed embodiments will be further explained withreference to the attached drawings. The drawings shown are notnecessarily to scale, with emphasis instead generally being placed uponillustrating the principles of the presently disclosed embodiments.

FIG. 1 shows hemorrhoidal pain level after treatment with compositionsof the present invention as gel and wipes, as compared to Preparation H.The data presented are the delta meaning the change from the previousday for each parameter measured.

FIG. 2 shows hemorrhoidal itching after treatment with compositions ofthe present invention as gel and wipes as compared to Preparation H. Thedata presented are the delta meaning the change from the previous dayfor each parameter measured.

FIG. 3 shows hemorrhoidal swelling after treatment with compositions ofthe present invention as gel and wipes, as compared to Preparation H.The data presented are the delta meaning the change from the previousday for each parameter measured.

FIG. 4 shows hemorrhoidal bleeding after treatment with compositions ofthe present invention as gel and wipes, as compared to Preparation H.The data presented are the delta meaning the change from the previousday for each parameter measured.

FIG. 5 shows hemorrhoidal discomfort after treatment with compositionsof the present invention as gel and wipes, as compared to Preparation H.The data presented are the delta meaning the change from the previousday for each parameter measured.

While the above-identified drawings set forth presently disclosedembodiments, other embodiments are also contemplated, as noted in thediscussion. This disclosure presents illustrative embodiments by way ofrepresentation and not limitation. Numerous other modifications andembodiments can be devised by those skilled in the art which fall withinthe scope and spirit of the principles of the presently disclosedembodiments.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides topical compositions comprising activepharmaceutical agents and uses thereof for treating anorectal andgenital disorders, including, but not limited to, hemorrhoids, analfissures, anal cracks, anal fistulas, anal abscesses, anal pruritus andother local anorectal lesions, genital warts, anal warts and herpes.

The topical compositions of the present invention are applied to agenital or anorectal surface for the treatment of genital or anorectaldisorders. Topical formulations currently available for use in thetreatment of anorectal or genital disorders typically comprise polarsolvents which enable the incorporation of the medicaments into theformulation. The major disadvantage of these currently available topicalformulations comprising polar solvents, e.g. ethanol, is their stingingeffect when applied to the skin or mucosal surface.

In contrast to currently available topical formulations, the topicalcompositions of the present invention comprise an aqueous phase whichallows dissolution and substantially homogeneous distribution of thepharmaceutical agents. In an embodiment, addition of water to thetopical composition reduces the use of stinging polar solvents and henceimproves the compliancy of the subject to be treated. It is furtherdisclosed that the topical compositions of the present invention, upondrying, form a film on a genital or anorectal mucosal surface and thusprovide a protective coating.

In addition, the topical compositions of the present invention, whendried, form a durable film which does not crack or flake off and remainsintact for more than 12 hours giving release of the pharmaceutical agentfor an extended period of time, thus leading to enhanced healing of theaffected areas.

The sustained or extended release of the pharmaceutical agent(s) fromthe compositions of the present invention enables methods of treatmentincluding less frequent administration (such as once daily, once everyother day or twice weekly) than existing commercially availableproducts, while achieving similar or better therapeutic results.

Further, the topical compositions of the present invention, when dried,form a flexible film, closely following irregularities of the bodysurface as well as movement of the body surface.

According to an aspect, the present invention provides a topicalanorectal or genital composition that includes:

-   -   from about 10.0% (w/w) to about 30.0% (w/w) of a silicone film        forming agent like trimethylsiloxysilicate;    -   from about 1.0% (w/w) to about 5.0% (w/w) of at least one        surfactant selected from the group consisting of sodium lauryl        sulfate, alkyl- and alkoxy-dimethicone copolyol, polysorbate and        a combination thereof;    -   from about 30.0% (w/w) to about 75.0% (w/w) of a non-polar        volatile siloxane solvent;    -   from about 15.0% (w/w) to about 40% (w/w) of water; and    -   from about 0.005% (w/w) to about 25.0% (w/w) of a pharmaceutical        agent selected from the group consisting of pramoxine,        phenylephrine, hydrocortisone, salicylic acid, nitroglycerine,        sildenafil, procaine, lidocaine, tetracaine, dibucaine,        prilocaine, phenacaine, benzyl alcohol, benzocaine, diperodon,        dyclonine, dimethisoquin, epinephrine, tetrahydrozoline        hydrochloride, an amphetamine, an antihistamine,        methylphenidate, mephedrone, oxymetazoline, pseudoephedrine,        psilocybin, ephedrine sulphate imiquimod, podophyllin,        podophylotoxin, trichloroacetic acid, bichloroacetic acid,        formic acid, fluorouracil, sinecatechins, plant extracts,        acyclovir, penciclovir, famciclovir, docosanol or their salts        and combinations thereof wherein the composition is sufficiently        designed to dry within 60 seconds after application to a genital        or anorectal surface to form a dried composition, and wherein        the dried composition forms:        -   (i) a flexible film, wherein the flexible film closely            follows irregularities of the surface as well as movement of            the surface, and        -   (ii) a durable film, wherein the durable film does not crack            or flake off and remains intact for more than 12 hours            giving release of the pharmaceutical agent for an extended            period of time.

According to an aspect, the present invention provides a topicalanorectal or genital composition that includes:

-   -   (i) at least one flexible film forming ingredient, (ii) at least        one surfactant, (iii) at least one non-polar volatile siloxane        solvent (iv) at least 15% (w/w) water, and (v) a therapeutically        effective concentration of at least one pharmaceutical agent,        wherein the composition is sufficiently designed to dry within        60 seconds after application to a genital or anorectal surface        to form a dried composition, wherein the dried composition        forms: (i) a flexible film, wherein the flexible film closely        follows irregularities of the surface as well as movement of the        surface, and (ii) a durable film, wherein the durable film does        not crack or flake off and remains intact for more than 12 hours        giving release of the pharmaceutical agent for an extended        period of time.

According to an embodiment, a topical composition of the presentinvention is in the form of an emulsion. In an embodiment, the emulsionis an oil-in-water emulsion. The emulsion may be in the form of aviscous gel (25000-45000 cP) or a liquid whose viscosity ranges from1-1.2 cP, close to the viscosity of water. While the gel is applied tothe skin or mucosal surface as such, the liquid emulsion is mainly usedfor the preparation of the wipes.

The topical compositions of the present invention can be administered asa gel, a wipe, a towellete, a water-based solution, a spray or a foam.

According to one embodiment, the at least one film forming ingredient isselected from the silicone resin group consisting of siloxysilicate,silsesquioxane or other silicone polymers. According to one embodiment,the siloxysilicate is trimethylsiloxysilicate. According to anadditional embodiment, the silsesquioxane is polymethylsilsesquioxane.

According to some embodiments, the at least one surfactant is an anionicsurfactant. The anionic surfactant can be selected from the groupconsisting of sodium alkyl sulfate, sodium alkyl sulfonate, sodium alkylaryl sulfonate, sodium stearate, dioctyl sodium sulfosuccinate, sodiumcholate, and any combination thereof. According to a certain embodiment,the sodium alkyl sulfate is sodium lauryl sulfate.

According to further embodiments, the at least one surfactant is anonionic surfactant. The nonionic surfactant can be selected from thegroup consisting of organosilicone surfactants, nonionic organicsurfactants and a combination thereof.

According to some embodiments, the organosilicone surfactant comprisesalkyl- and alkoxy-dimethicone copolyol. According to furtherembodiments, the alkyl- and alkoxy-dimethicone copolyol is cetyldimethicone copolyol. According to a certain embodiment, the cetyldimethicone copolyol is Cetyl PEG/PPG-10/1 Dimethicone.

According to further embodiments, the nonionic organic surfactant isselected from the group consisting of polysorbate, glyceryl stearate,polyoxyethylene (POE) fatty acid ester, poly(oxyethylene) alkylyl ether,polyethoxylene castor oil derivative, PEG-6 octanoic/decanoicglycerides, polyoxyethylene glycerol trioleate, decaglycerolmono/dioleate, and any combination thereof. The polysorbate can beselected from the group consisting of polyoxyethylene sorbitanmonolaurate (Tween 20), polyoxyethylene sorbitan monopalmitate (Tween40), polyoxyethylene sorbitan monostearate (Tween 60) andpolyoxyethylene sorbitan monooleate (Tween 80).

According to still further embodiments, the at least one surfactant is acationic surfactant, an amphoteric surfactant, or a combination thereof.

According to additional embodiments, the volatile solvent is a non-polarvolatile siloxane, such as methylsiloxane or a polydimethylsiloxane.According to some embodiments, the volatile polydimethylsiloxane is alinear polydimethylsiloxane or a cyclic polydimethylsiloxane. Accordingto further embodiments, the volatile polydimethylsiloxane is selectedfrom the group consisting of hexamethyldisiloxane,heptamethyloctyltrisiloxane octamethylcyclotetrasiloxane,octamethyltrisiloxane, decamethylcyclopentasiloxane,decamethyltetrasiloxane, dodecamethylpentasiloxane,dodecamethylcyclohexasiloxane, and a combination thereof. According to acertain embodiment, the volatile polydimethylsiloxane ishexamethyldisiloxane.

According to further embodiments, the volatile solvent is a volatilealiphatic hydrocarbon selected from the group consisting of alkanes,alkenes, alkynes, and mixtures thereof. According to yet furtherembodiments, the alkane is selected from the group consisting ofpentane, isooctane, isododecane, isohexadecane and a combinationthereof. According to a certain embodiment, the volatile aliphatichydrocarbon is isooctane. According to another embodiment, the volatilesolvent is a combination of a siloxane and isooctane.

According to additional embodiments, the pharmaceutical agent isselected from the group consisting of anesthetic agents,vasoconstrictors, protectants, an immunomodulator, a cytotoxin,antipruritic agents, immunomodulators, cytotoxins, anti-inflammatoryagents, muscle relaxants, and a combination thereof. Each possibility isa separate embodiment of the invention.

The anesthetic agent can be selected from the group consisting ofpramoxine, procaine, lidocaine, tetracaine, dibucaine, prilocaine,phenacaine, benzyl alcohol, benzocaine, diperodon, dyclonine,dimethisoquin, salts thereof, and a combination thereof. According to acertain embodiment, the anesthetic agent is pramoxine. According to someembodiments, the anesthetic agent is present in the topical compositionin an amount ranging from about 0.15% (w/w) to about 25% (w/w).

According to further embodiments, the vasoconstrictor is selected fromthe group consisting of phenylephrine, phenylephrine hydrochloride,epinephrine, epinephrine hydrochloride, tetrahydrozoline hydrochloridean amphetamine, an antihistamine, methylphenidate, mephedrone,oxymetazoline, pseudoephedrine, psilocybin, ephedrine sulphate, and acombination thereof. According to an exemplary embodiment, thevasoconstrictor is phenylephrine. According to some embodiments, thevasoconstrictor is present in the topical composition in an amountranging from about 0.005% (w/w) to about 2% (w/w).

According to a certain embodiment, the pharmaceutical topicalcomposition comprises a combination of pramoxine and phenylephrine.

According to further embodiments, the antipruritic agent is selectedfrom the group comprising corticosteroid, camphor, juniper tar, mentholand a combination thereof. According to a certain embodiment, thecorticosteroid is hydrocortisone. According to some embodiments, theantipruritic agent is present in the topical composition in an amountranging from about 0.1% (w/w) to about 5% (w/w).

According to yet further embodiments, the muscle relaxant is nifedipine,diltiazem verapamil, nitroglycerin, sildenafil, or a salt thereof.According to a certain embodiment, the muscle relaxant is sildenafilcitrate. According to some embodiments, the muscle relaxant is presentin the topical composition in an amount ranging from about 0.1% (w/w) toabout 15% (w/w).

According to still further embodiments, the anti-inflammatory agent isselected from the group consisting of salicylic acid, indomethacin,sodium indomethacin trihydrate, salicylamide, naproxen, colchicine,fenoprofen, sulindac, diflunisal, diclofenac, indoprofen and sodiumsalicylamide. According to still further embodiment, theanti-inflammatory agent is salicylic acid.

According to some embodiments, a topical composition of the presentinvention can further comprise an astringent, a keratolytic agent, anantibiotic agent, an antiseptic agent, an antioxidant, a keratolytic, aprotectant, an astringent or a combination thereof. Each possibility isa separate embodiment of the invention.

According to some embodiments, a pharmaceutical topical composition ofthe present invention can further comprise an additive/excipientselected from the group consisting of a dimethicone/vinyl dimethiconecrosspolymer, a silicone gum blend, a gelling agent and a combinationthereof. Each possibility is a separate embodiment of the invention.

According to a certain embodiment, the dimethicone/vinyl dimethiconecrosspolymer comprises bis-vinyldimethicone, vinyldimethicone andhydrogen dimethicone.

According to additional embodiments, the silicone gum blend comprises ablend of high and low molecular weight silicones. According to a certainembodiment, the silicone gum blend comprises cyclopentasiloxane anddimethiconol.

According to additional embodiments, the gelling agent is a cellulosederivative. According to a certain embodiment, the cellulose derivativeis hydroxypropyl methyl cellulose. According to other embodiments, thegelling agent is selected from the group consisting of carbomer,carbomer copolymers, gelatin, aluminum monostearate, dextrin, sodiumalginate, alginic acid, pectin, acacia, alginic acid, carrageenan,xanthan, tragacanth, magnesium aluminum silicate, bentonite, poloxamers,polyvinyl alcohol, and a combination thereof.

According to some embodiments, a topical composition comprises: (i)trimethylsiloxysilicate; (ii) a surfactant selected from the groupconsisting of an anionic surfactant, a nonionic surfactant and acombination thereof; (iii) a volatile solvent selected from the groupconsisting of a siloxane such as methylsiloxane or apolydimethylsiloxane, an aliphatic hydrocarbon, and a combinationthereof, (iv) water; and (v) at least one pharmaceutical agent selectedfrom the group consisting of an anesthetic agent, a vasoconstrictor, anantipruritic agent, an immunomodulator, a cytotoxin, an anti-acne agent,an anti-inflammatory agent, a muscle relaxant, and a combinationthereof. According to a certain embodiment, the surfactant is an anionicsurfactant. According to some embodiments, the topical compositionfurther comprises an additive selected from the group consisting of adimethicone/vinyl dimethicone crosspolymer, a silicone gum blend, agelling agent and a combination thereof.

According to some embodiments, a topical composition comprises: (i)about 10% (w/w) to about 40% (w/w) of trimethylsiloxysilicate; (ii)about 0.5% (w/w) to about 7% (w/w) of a surfactant selected from thegroup consisting of sodium lauryl sulfate, alkyl- and alkoxy-dimethiconecopolyol, polysorbate, and a combination thereof; (iii) about 30% (w/w)to about 80% (w/w) of a volatile solvent, selected from the groupconsisting of a siloxane such as methylsiloxane or apolydimethylsiloxane, volatile aliphatic hydrocarbon and a combinationthereof; (iv) about 20% (w/w) to about 40% (w/w) of water; and (v) about0.005% (w/w) to about 25% (w/w) of at least one pharmaceutical agent,selected from the group consisting of pramoxine, phenylephrine,hydrocortisone, salicylic acid, nitroglycerine, sildenafil citrate, anda combination thereof. According to a certain embodiment, the at leastone surfactant is sodium lauryl sulfate. According to anotherembodiment, the surfactant is a combination of sodium lauryl sulfate andcetyl dimethicone copolyol. According to additional embodiments, thesurfactant is a combination of polysorbate and cetyl dimethiconecopolyol. According to some embodiments, cetyl dimethicone copolyol isCetyl PEG/PPG-10/1 Dimethicone. According to some embodiments,polydimethylsiloxane is hexamethyldisiloxane. According to additionalembodiments, volatile aliphatic hydrocarbon is isooctane. According tosome embodiments, the topical composition further comprises about 0.2%(w/w) to about 15% (w/w) of an additive selected from the groupconsisting of bis-vinyldimethicone, vinyldimethicone and hydrogendimethicone; cyclopentasiloxane and dimethiconol; hydroxypropyl methylcellulose; and a combination thereof. According to some embodiments,bis-vinyldimethicone, vinyldimethicone and hydrogen dimethicone can bepresent in the topical composition in an amount ranging from about 5.0%(w/w) to about 15% (w/w). According to further embodiments,cyclopentasiloxane and dimethiconol can be present in the topicalcomposition in an amount ranging from about 0.5% (w/w) to about 2.5%(w/w). According to still further embodiments, hydroxypropyl methylcellulose can be present in the topical composition in an amount rangingfrom about 0.05% (w/w) to about 5% (w/w).

According to some embodiments, a topical composition comprises: (i)about 20% (w/w) trimethylsiloxysilicate; (ii) about 3.0% (w/w) sodiumlauryl sulfate; (iii) about 267% (w/w) hexamethyldisiloxane and 20%(w/w) isooctane; (iv) about 30% (w/w) water; and (v) about 1% (w/w)pramoxine as the pharmaceutical agent. Alternatively, the pharmaceuticalagent is phenylephrine in an amount of about 0.05% (w/w). Furtheralternatively, the pharmaceutical agent is a combination of about 1%(w/w) pramoxine and about 0.25% (w/w) phenylephrine. Still furtheralternatively, the pharmaceutical agent is hydrocortisone in an amountof about 1% (w/w), or salicylic acid in an amount of about 1-20% (w/w),or nitroglycerine in an amount of about 0.2% (w/w) to about 0.5% (w/w),or sildenafil citrate in an amount of about 10%, or nifedipine in anamount of about 0.1% (w/w) to about 5% (w/w) or diltiazem in an amountof about 0.1-5% w/w, or verapamil in an amount of about 0.1% (w/w) toabout 5.0% (w/w) or a combination thereof.

According to a certain embodiment, a topical composition comprises: (i)about 20% (w/w) trimethylsiloxysilicate; (ii) about 3.0% (w/w) sodiumlauryl sulfate; (iii) about 26% (w/w) hexamethyldisiloxane and 20% (w/w)isooctane; (iv) about 30% (w/w) water; (v) about 1% (w/w) pramoxine; and(vi) about 0.05% (w/w) phenylephrine.

According to further embodiments, a topical composition comprises: (i)about 20% (w/w) trimethylsiloxysilicate; (ii) about 1.5% (w/w) sodiumlauryl sulfate; (iii) about 4% (w/w) Cetyl PEG/PFG-10/1 Dimethicone (iv)about 24% (w/w) hexamethyldisiloxane and 20% (w/w) isooctane; (v) about30% (w/w) water; and (vi) about 1% (w/w) pramoxine as the pharmaceuticalagent. Alternatively, the pharmaceutical agent is phenylephrine in anamount of about 0.25% (w/w). Further alternatively, the pharmaceuticalagent is a combination of about 1% (w/w) pramoxine and about 0.25% (w/w)phenylephrine. Still further alternatively, the pharmaceutical agent ishydrocortisone in an amount of about 1% (w/w), yet further alternativelythe pharmaceutical agent is imiquimod in an amount of about 4.0% (w/w)to about 5.0% (w/w), or podophyllotoxin in an amount of about 0.5%(w/w), or 5-fluorouracil in an amount of about 0.1% (w/w) to about 10%(w/w), or salicylic acid in an amount of about 1.0% (w/w) to about 20%(w/w), or nitroglycerine in an amount of about 0.2% (w/w) to about 0.5%(w/w), or sildenafil citrate in an amount of about 10% (w/w), ornifedipine in an amount of about 0.1% (w/w) to about 5% (w/w) ordiltiazem in an amount of about 0.1% (w/w) to about 5.0% (w/w), orverapamil in an amount of about 0.1% (w/w) to about 5.0% (w/w) or acombination thereof.

According to still further embodiments, a topical composition comprises:(i) about 20% (w/w) trimethylsiloxysilicate; (ii) about 1.5% (w/w) Tween80; (iii) about 4% (w/w) Cetyl PEG/PPG-10/1 Dimethicone (iv) about 24%(w/w) hexamethyldisiloxane and 20% (w/w) isooctane; (v) about 30% (w/w)water; and (vi) about 1% (w/w) pramoxine as the pharmaceutical agent.Alternatively, the pharmaceutical agent is phenylephrine in an amount ofabout 0.25% (w/w). Further alternatively, the pharmaceutical agent is acombination of about 1% (w/w) pramoxine and about 0.25% (w/w)phenylephrine. Still further alternatively, the pharmaceutical agent ishydrocortisone in an amount of about 1% (w/w), or salicylic acid in anamount of about 1.0% (w/w) to about 20% (w/w), or nitroglycerine in anamount of about 0.2% (w/w) to about 0.5% (w/w), or sildenafil citrate inan amount of about 10% (w/w), or nifedipine in an amount of about 0.1%(w/w) to about 5.0% (w/w) or diltiazem in an amount of about 0.1% (w/w)to about 5.0% (w/w), or verapamil in an amount of about 0.1% (w/w) toabout 5.0% (w/w0 or a combination thereof.

According to some embodiments, the pH of a topical composition of thepresent invention is from about 3.5 to about 5. According to otherembodiments, the pH of a topical composition of the present invention isfrom about 4.0 to about 4.6. According to additional embodiments, the pHof a topical composition of the present invention is from about 4.2 toabout 4.4. According to some embodiments, the pH is maintained usingcitrate buffer.

According to another aspect, the present invention provides a method oftreating or preventing a topical disorder, the method comprising thestep of topically applying to the skin or mucosal surface a mucosalsurface of a subject in need of such treatment a therapeuticallyeffective amount of a topical composition of the present invention.

According to some embodiments, the topical disorder is selected from thegroup consisting of hemorrhoids, anal fissures, anal cracks, analfistulas, anal abscesses and anal pruritus dermatitis, acne, rosacea,onychomycosis, pityriasis, actinic keratosis, eczema, erythema,urticaria, common warts, genital warts, anal warts and herpes.

According to a certain embodiment, the topical disorder is an anorectaldisorder selected from hemorrhoids, fissure and anal pruritus.

According to a certain embodiment, the topical disorder is genitalwarts, anal warts and herpes.

According to a certain embodiment, the topical disorder is acne orrosacea.

According to additional embodiments, if the anorectal disorder ishemorrhoids, the pharmaceutical agent is an anesthetic agent, avasoconstrictor, or a combination thereof. According to a certainembodiment, the topical composition for use in treating or preventinghemorrhoids comprises a combination of about 1% (w/w) pramoxine andabout 0.25% (w/w) phenylephrine.

According to some embodiments, if the anorectal disorder is analpruritus, the topical composition for use in treating or preventing analpruritus comprises an antipruritic agent. According to a certainembodiment, the antipruritic agent is hydrocortisone in an amount ofabout 1% w/w hydrocortisone.

According to some embodiments, if the anorectal disorder is analfissures, the pharmaceutical agent to be administered is a musclerelaxant. According to an exemplary embodiment, the topical compositioncomprises about 0.1% (w/w) to about 0.5% (w/w) nifedipine, or about 0.2%(w/w) to about 0.5% (w/w) nitroglycerine, or about 10% (w/w) sildenafilcitrate or diltiazem in an amount of about 0.1% (w/w) to about 5.0%(w/w), or verapamil in an amount of about 0.1% (w/w) to about 5.0%(w/w).

According to one embodiment, the subject to be treated is a human being.According to another embodiment, the subject to be treated is an animal.

According to yet another aspect, the present invention provides a kitcomprising a topical composition of the present invention, acontainer-applicator device suitable for storage and application of thecomposition to the genital or anorectal region, and instructions foradministering the topical composition to a subject in need thereof.

According to some embodiments, the container-applicator device isselected from the group consisting of a single use wipe, a syringe, adropper, a spray dispenser, a swab, a compressible bottle or tube, aspatula, a suppository insertion tube, an extrusion tube, a pumpdispenser, a pressurized dispenser and an inflatable member.

According to another aspect, the present invention provides a topicalcomposition for use in treating or preventing an anorectal or genitaldisorder.

Other objects, features and advantages of the present invention willbecome clear from the following description and claims.

A topical composition of the present invention comprises at least onefilm forming agent, at least one surfactant, at least one non-polarvolatile solvent, water and at least one pharmaceutically active agent.One such film forming agent may be a silicone resin. The topicalcomposition can further comprise additives, such as dimethicone/vinyldimethicone crosspolymers, silicone gum blends and gelling agents.

The term “film forming agent” or “film forming ingredient” or “filmformer”, as used herein, means an inactive ingredient such as a siliconeresin that after dissolution in at least one solvent and application ona substrate leaves a film on the substrate to which it is applied, forexample once the at least one solvent evaporates, absorbs and/ordissipates on the substrate.

The anorectal disorders have a unique feature which is only shared withtopical use on skin and joints. Anal fissure (a tear in the anus) andhemorrhoids both extend significantly during defecation, which causesreopening of the anal fissure, bleeding, itching and pain. Therefore,flexible films possess a distinct advantage for the treatment ofanorectal disorders such as anal fissure and hemorrhoids, providing abetter protection of the wound, and reduction of bleeding, itching andpain during extension that occurs during defecation.

Silicone resins, such as polydimethylsiloxane andpolymethylsilsesquioxane have a unique semi-organic structure and areflexible.

While using film forming agents in the instant invention, it isdesirable to use such flexible film forming agents and formulate them insuch compositions which produce flexible and durable films. In anembodiment, there are provided flexible and durable film formingcompositions, providing beneficial therapeutic effects like reducedbleeding, pain and itching.

The durability and flexibility of the films formed from the compositionsof the present invention on drying were investigated by applying thecomposition L of Table 2, Example 3 on the elbow, neck and internal partof the arm of a patient. Shortly thereafter (about 20 seconds) thecomposition dried and left a thin film on the skin. The films wereexamined after 12, 18 and 24 hrs for durability and flexibility. Duringthis period the patient carried out their usual daily activities andtook one shower.

It was found that the films remained intact after 12, 18 and 24 hrs. Thefilms did not fall off the body surface and did not crack or flake off.It was found that the films remained flexible after 12, 18 and 24 hrs.The films closely followed the patient's skin irregularities as well asskin movement throughout the day during normal activity. The skin underthe film was slightly pale, which shows the vasoconstrictorphenylephrine was still active after 24 hrs. After 24 hrs, the film wasremoved from the skin and tested by high performance liquidchromatography (HPLC), whereupon significant amounts of the two actives(pramoxine and phenylephrine) were found in the film despite theextended period of time.

The film formed on the skin or mucosal surface allows the tissues to“breathe”, which is beneficial because of the extended period of timethe film stays on the tissues.

The compositions of the instant invention dry relatively fast afterapplication on the skin or mucosal surface between 5 seconds and 1minute to form a durable and elastic film.

The film formed on the substrate is substantially dry, which means itcontains less than 10% volatiles. In an embodiment, the dried filmcontains less than 5% volatiles. In an embodiment, the dried filmcontains less than 2% volatiles. The important aspect of thesubstantially dry films of this invention, whatever the percentage ofvolatiles left, is that they feel dry to touch and do not soil, stain orotherwise absorb into the underwear.

Most of the commercially available topical formulations are in the formof cream, ointment, enema, suppositories or other forms ofadministration which leave on the anus and rectum a greasy deposit whichis very problematic, because of the potential of staining, soiling orotherwise absorbing into the underwear.

In an embodiment, there are provided non-soiling compositions, affordingconvenience for the patient, improving patient compliance and avoidingembarrassment.

Commercially available anorectal products and compositions are usuallyapplied several times daily and before each defecation.

Thus, for example, Preparation H® Maximum Strength, containingphenylephrine HCl 0.25% and Pramoxine HCl 1% is applied “up to 4 timesdaily, especially at night, in the morning or after each bowelmovement”.

It has been surprisingly found that compositions of the instantinvention may be administered less often than commercial productscontaining the same pharmaceutically active agents in the sameconcentrations.

Thus, in a comparative clinical study, composition PP-110 (see Example8) of the instant invention containing HCl 0.25% and Pramoxine HCl 1%(the same pharmaceutical actives in the same concentrations asPreparation H®) showed comparable or superior results compared to thePreparation-H arm in one or both of PP-110 arms. This includes pain,itching, swelling, bleeding and discomfort, and was achieved even thoughPP-110 was applied once daily and Preparation-H was applied 4 times perday. It is believed that, as a result, the patient is exposed to a muchlower dose of the active pharmaceutical ingredient(s).

Without wishing to be bound by theory, the inclusion of the activepharmaceutical in the flexible film seems to have a long-acting orsustained release effect, achieving comparable or superior resultscompared to similar commercial products, while exposing the patient tosmaller amounts of the active pharmaceutical ingredient(s).

In an embodiment, there are provided anorectal or genital compositionsachieving a similar or better therapeutic effect than a commerciallyavailable composition comprising the same active pharmaceutical agent(s)in the same concentrations wherein applied several times daily.

In an embodiment, there are provided once daily anorectal or genitaltopical compositions comprising:

-   -   (i) at least one flexible film forming ingredient;    -   (ii) at least one surfactant;    -   (iii) at least one non-polar volatile solvent;    -   (iv) at least 15% (w/w) water; and    -   (v) a therapeutically effective concentration of at least one        pharmaceutical agent,    -   wherein the composition is sufficiently designed to dry within        60 seconds after application to a mucosal surface of an        anorectal or genital region to form a dried composition, wherein        the dried composition forms: (i) a flexible film, wherein the        flexible film closely follows irregularities of the mucosal        surface as well as movement of the mucosal surface, and (ii) a        durable film, wherein the durable film does not crack or flake        off and remains intact for more than 12 hours giving release of        the pharmaceutical agent for an extended period of time. The        dried film in non-soiling.

The above compositions may be topically administered even less oftenthan once daily, such as once every other day or twice weekly.

In an embodiment, there are provided once daily anorectal or genitaltopical compositions comprising:

-   -   (i) at least one flexible film forming ingredient;    -   (ii) at least one surfactant;    -   (iii) at least one non-polar volatile solvent;    -   (iv) at least 15% (w/w) water;    -   (v) at least one viscosity modifier; and    -   (vi) a therapeutically effective concentration of at least one        pharmaceutical agent,    -   wherein the composition is sufficiently designed to dry within        60 seconds after application to a mucosal surface of an        anorectal or genital region to form a dried composition, wherein        the dried composition forms: (i) a flexible film, wherein the        flexible film closely follows irregularities of the mucosal        surface as well as movement of the mucosal surface, and (ii) a        durable film, wherein the durable film does not crack or flake        off and remains intact for more than 12 hours giving release of        the pharmaceutical agent for an extended period of time. The        dried film in non-soiling.

In an embodiment there is provided a method of treatment of anorectal orgenital disorders, the method comprising the step of topically applyingonce daily, or once every other day or twice weekly to an anorectal orgenital region of a subject in need of such treatment, a therapeuticallyeffective concentration of a topical composition of the presentinvention.

The selection of the inactive pharmaceutical ingredients and theirconcentration has an impact on the therapeutic effect of thecompositions, so that extensive experimentation was needed until theoptimal compositions were developed. Thus, for example, lowconcentrations of water result in incomplete solubilization of theactive(s) and high-water concentrations lead to slow rate of drying.

It has been surprisingly found that when a topical composition of thepresent invention is formulated for use as a wipe, the addition ofinactive ingredients like Pemulen®, have a profound effect on theviscosity of the compositions, lowering the viscosity even atconcentrations below 0.1% (w/w). Therefore, Pemulen® may be included inthe composition for the wipes, which requires a lower viscosity.

In an embodiment, the film forming agents used in the compositions ofthe present invention are non-polymerizable and therefore, unlike thepolymerizable agents are less sensitive to moisture, more stable andmore suitable for repeated use.

The term “volatile solvent”, as used herein, means that the solvent hasa measurable vapor pressure. Suitable volatile solvents are non-polarsolvents.

Some of the film forming agents according to the present invention aresilicone resins. The non-limiting examples of silicone resins useful inthe compositions of the invention are siloxysilicates, silsesquioxanes(usually denoted as T-resins) and a combination thereof. Onenon-limiting example of a siloxysilicate in accordance with the presentinvention is trimethylsiloxysilicate, which may be represented by thefollowing formula:

[(CH3)3-Si—O]x-(SiO4/2)y

wherein x and y may, for example, range from 50 to 80. Suchsiloxysilicates are commercially available from General Electric and DowCorning under the trade name Resin MQ®. One non-limiting example ofsilsesquioxane is polymethylsilsesquioxane. Trimethylsiloxysilicate andpolymethylsilsesquioxane are widely used in cosmetic industry due totheir film forming properties, as described, for example, in U.S. Pat.Nos. 7,879,316 and 7,879,346 and U.S. Patent Application Publication No.2005/0201961. The present invention discloses for the first time the useof trimethylsiloxysilicate for therapeutic applications, inter alia, fortreatment of anorectal or genital disorders. Trimethylsiloxysilicate issoluble in the volatile solvent of a topical composition of the presentinvention. The amount of the silicone resin film forming agent in thecomposition is determined based on the desired adhesion properties ofthe dried film to the target surface. The amount depends, inter alia, onthe target surface, the condition to be treated, and the amount ofcomposition ingredients. The amount of the silicone resin film formingagent further defines the viscosity of the topical composition. Theamount of the silicone resin film forming agent in the compositiontypically ranges from about 10% to 40% w/w. The term “about” as usedherein denotes ±10% of the value indicated.

In an embodiment, the volatile solvent useful for dissolving thesilicone resin is chosen from volatile silicone or volatile aliphatichydrocarbon. In an embodiment, water solubility of the volatile solventis less than about 0.1%. According to some embodiments, the volatilesilicone solvent is a linear or cyclic polydimethylsiloxane, having from2 to 9 silicon atoms, these silicones being optionally substituted withalkyl or alkoxy groups of 1 to 10 carbon atoms. The non-limitingexamples of a siloxane such as methylsiloxane or a polydimethylsiloxanein accordance with the present invention are hexamethyldisiloxane,heptamethyloctyltrisiloxane octamethylcyclotetrasiloxane,octamethyltrisiloxane, decamethylcyclopentasiloxane,decamethyltetrasiloxane, dodecamethylpentasiloxane,dodecamethylcyclohexasiloxane, and mixtures thereof. A suitablepolydimethylsiloxane used in the compositions is hexamethyldisiloxane.

The volatile solvent can further comprise a volatile aliphatichydrocarbon. The aliphatic hydrocarbon in accordance with the presentinvention may be any aliphatic hydrocarbon, including an alkane, amixture of alkanes, an alkene, a mixture of alkenes, an alkyne, amixture of alkynes, an ester or a mixture thereof. In an embodiment, thealiphatic hydrocarbon is an alkane such as pentane, isooctane,isododecane, isohexadecane or a mixture thereof. According to a certainembodiment, the aliphatic hydrocarbon is isooctane. The volatile esteruseful for dissolving the film former may be a branched ester, such asisohexyl or isodecyl neopentanoate and mixture thereof.

The volatile solvent may comprise a volatile silicone, a volatilealiphatic hydrocarbon or a mixture thereof. According to a certainembodiment, the volatile solvent comprises methylsilozane or ahexamethyldisiloxane and isooctane.

According to some embodiments, the presence of water in a topicalcomposition of the present invention allows dissolution of thepharmaceutically active agents, which are not soluble in the non-polarvolatile solvents used for dissolving the film-former, thus avoiding theneed to use polar solvents. As the pharmaceutically active agents arecompletely dissolved in the compositions of the present invention and donot precipitate or crystallize on drying, the resulting essentially dryfilms comprising the active(s) are clear, transparent and not “whitefilms”.

The emulsion can be a water-in-oil or oil-in-water emulsion. Accordingto exemplary embodiments, a topical composition of the present inventionis an oil-in-water emulsion, wherein the aqueous phase includes thepharmaceutical agents dissolved therein and the oil phase includes thefilm forming agent dissolved in the volatile solvent. The oil-in-wateremulsion allows the film former and the pharmaceutical active agents tobe homogeneously dispersed in the topical composition. The stableemulsion provides fine dispersion of the emulsion ingredients in thetopical composition, in the container-applicator device and upon theapplication to the target surface, such that once the volatile solventand water evaporate both the film former and the pharmaceutical activeingredients remain finely dispersed on the target surface. The stableemulsion prevents clamping, floating and/or precipitation of the polaractive ingredients in the non-polar volatile solvents. The presence ofthe aqueous phase in the topical composition further obviates the use ofpolar solvents, formerly required to dissolve and dispersepharmaceutical active ingredients in silicone based liquid bandages.

The amount of the volatile solvent and water affects the viscosity andevaporation time of the topical composition when applied to a targetsurface. The amount of the volatile solvent and water is determined soas to adjust the viscosity and evaporation time to desired values. Theamount of volatile solvent and water further affects the morphology ofthe silicone/water emulsion. The amount of the volatile solvent can beadjusted to obtain the desired emulsion type. The amount of the volatilesolvent in the composition typically ranges from about 30% to about 80%w/w. The amount of water can be adjusted to obtain the desired emulsiontype. The amount of water in the composition typically ranges from about20% (w/w) to about 40% (w/w).

The topical compositions of the present invention further comprise atleast one surfactant. Addition of the surfactant allows mixing of thesilicone and the aqueous phases, producing a silicone/water emulsion.Addition of the surfactant further allows the emulsion stabilization. Asdescribed hereinabove, the obtained emulsion may be an oil-in-wateremulsion, wherein the aqueous phase includes dissolved pharmaceuticalingredients and finely dispersed volatile solvent phase, containing thedissolved film former.

The surfactant is selected from the group consisting of an anionicsurfactant, a non-ionic surfactant, selected from organosiliconesurfactant or nonionic organic surfactant, a cationic surfactant, anamphoteric surfactant and a combination thereof. Each possibility is aseparate embodiment of the invention.

The anionic surfactants usable in the compositions of the presentinvention include sodium alkyl sulfates, such as, but not limited tosodium lauryl sulfate; sodium alkyl sulfonates; sodium alkyl arylsulfonates, such as sodium dodecyl benzene sulfonate and the like;sodium stearate; dioctyl sodium sulfosuccinate; sodium cholate; and acombination thereof.

Examples of suitable organosisilicone surfactants include, but are notlimited to dimethicone copolyols such as: alkoxy dimethicone copolyols,alkyl and alkoxy-dimethicone copolyols, silicones having pendanthydrophilic moieties such as linear silicones having pendant polyethergroups, branched polyether and alkyl modified silicones, branchedpolyglycerin and alkyl modified silicones. A suitable dimethiconecopolyol is cetyl dimethicone copolyol, such as Cetyl PEG/PPG-10/1Dimethicone sold under the name Abil EM-90. Other suitable dimethiconecopolyols include branched polyether and alkyl modified silicones suchas Lauryl PEG-9 Polydimethylsiloxyethyl Dimethicone sold under the nameKF-6038, and branched polyglycerin and alkyl modified silicones such asLauryl Polyglyceryl-3 Polydimethylsiloxyethyl Dimethicone sold under thename KF-6105. Additional dimethicone copolyols useful in thecompositions of the present invention include bis-PEG/PPG-14/dimethiconecopolyol sold under the name Abil EM-97 and the polyglyceryl-4isostearate/cetyl dimethicone copolyol/hexyl laurate mixture sold underthe name Abil WE 09. Another suitable dimethicone copolyol is PEG-9Polydimethylsiloxyethyl Dimethicone sold under the name KF-6028. AbilEM-90, Abil EM-97 and. Abil WE 09 are available from Evonik GoldschmidtGmbH of Essen, Germany. KF-6038 are KF-6105 are available from Shin-EtsuSilicones of Akron, Ohio.

Non-limiting examples of possible non-ionic organic surfactants includepolysorbates, such as polyoxyethylene sorbitan monolaurate (Tween 20),polyoxyethylene sorbitan monopalmitate (Tween 40), polyoxyethylenesorbitan monostearate (Tween 60) and polyoxyethylene sorbitan monooleate(Tween 80); glyceryl stearate; polyoxyethylene (POE) fatty acid esters,such as Myrj 45, Myrj 49, Myrj 52 and Myrj 59; poly(oxyethylene) alkylylethers, such as poly(oxyethylene) cetyl ether (Brij 52, Brij 56, Brij58), poly(oxyethylene) palmityl ether, polyethylene oxide hexadecylether, polyethylene glycol cetyl ether, and the like; polyethoxylenecastor oil derivatives, such as Cremophor EL, ELP and RH 40; PEG-6octanoic/decanoic glycerides, such as Softigen 767 and the like;polyoxyethylene glycerol trioleate, such as but not limited to Tagat TO;decaglycerol mono/dioleate, such as Caprol PGE860 and the like; and acombination thereof. The nonionic organic surfactants may furthercomprise sorbitan fatty acid esters, such as sorbitan monolaurate (Span20), sorbitan monopalmitate (Span 40), sorbitan monooleate (Span 80),sorbitan monostearate (Span 60); mono/diglycerides of octanoic/dectanoicacids, such as but not limited to Imwitor-742, Imwitor-308, and acombination thereof.

Non-limiting examples of possible cationic surfactants includephosphatides, such as phosphatidyl choline and the like; quaternaryammonium cationic surfactants, such as hexadecyltrimethyl ammoniumbromide and the like; pyrimidinium cationic surfactants, such as, butnot limited to dodecyl pyridinium chloride; and a combination thereof.

The amphoteric surfactant may include lecithine, N-dodecyl alanine,cocamidopropyl amino betaine or a combination thereof.

The type and the amount of surfactant may be determined so as to obtainthe Hydrophile-Liphophile Balance (HLB) of the surfactant or thesurfactant mixture suitable for the oil-in-water systems.

According to some embodiments, the surfactant used in the compositionsof the present invention is an anionic surfactant. According toadditional embodiments, the surfactant may further comprise nonionicsurfactant. The nonionic surfactant may be selected from the groupconsisting of nonionic organic surfactant, organosilicone surfactant anda combination thereof. According to other embodiments, the surfactant inthe compositions of the present invention is a nonionic surfactant.

According to an embodiment, the surfactant is sodium alkyl sulfate, suchas sodium lauryl sulfate. According to other embodiments, the surfactantis a combination of sodium alkyl sulfate and alkyl andalkoxy-dimethicone copolyol, for example, sodium lauryl sulfate andCetyl PEG/PPG-10/1 Dimethicone. According to other embodiments, thesurfactant is selected from polyoxyethylene sorbitan monolaurate (Tween20), polyoxyethylene sorbitan monopalmitate (Tween 40), polyoxyethylenesorbitan monostearate (Tween 60), polyoxyethylene sorbitan monooleate(Tween 80) or any mixture thereof. According to further embodiments, thesilicone surfactant is a combination of polysorbate alkyl andalkoxy-dimethicone copolyol, for example, polyoxyethylene sorbitanmonooleate (Tween 80) and Cetyl PEG/PPG-10/1 Dimethicone.

A topical composition of the present invention may further comprise anadditive selected from the group consisting ofdimethicone/vinyldimethicone crosspolymers, silicone gum blends, gellingagents, and a combination thereof.

The dimethicone/vinyldimethicone crosspolymer is available, for example,from Dow Corning as Dow Corning 9506 Cosmetic Powder. According to otherembodiments, the dimethicone/vinyldimethicone crosspolymer can bepresent in the compositions of the present invention in a form oftwo-part silicone elastomer. Without being bound to any mechanism ofaction, the addition of two-part silicone elastomers to the topicalcomposition can provide enhanced film adhesion onto the target surfaceand can allow reduction of skin strain, which may be caused by thesilicone resin. The two-part silicone elastomers form a crosspolymernetwork by addition reaction, upon mixing the two parts, enhancing thecomposition adhesive properties. One part of the two-part siliconeelastomer usually contains vinyl endblocked silicone polymer and acatalyst suitable for promoting the addition reaction and another partcontains vinyl endblocked silicone polymer and silicone polymer carryingSiH groups. These two parts are stored separately before use and thecrosslinking reaction starts upon mixing the two parts in a definedratio. The ratio of the two parts is usually 50:50 and the crosslinkingreaction may proceed at room temperature (25±5° C.). The two-partsilicone elastomers may comprise dimethicone, hydrogen dimethicone,vinyldimethicone, bis-vinyldimethicon and phenyltrimethicone. Accordingto a certain embodiment, the topical composition of the presentinvention comprises bis-vinyldimethicone as the first part of thetwo-part silicone elastomers and vinyldimethicone and hydrogendimethicone as the second part. The first part can further contain aplatinum catalyst. The bis-vinyldimethicone, vinyldimethicone andhydrogen dimethicone are available, for example, from KCC as SM9010™ orSM9020™. The amount of the dimethicone/vinyldimethicone in thecomposition may be in a range from about 5% (w/w) to about 15% (w/w).

The topical compositions of the present invention may further comprise asilicone gum blend. Without being bound to any mechanism of action, theaddition of the silicone gum blend provides enhancement of silkiness ofthe film. Silicone gum blend may be a blend of a high molecular weightand a low molecular weight silicone. In an embodiment, the averagemolecular weight of the high molecular weight silicone is 100,000 orgreater. In an embodiment, the average molecular weight of the lowmolecular weight silicone is 10,000 or less. High molecular and lowmolecular weight silicones may comprise dimethicone and/or dimethiconol.The non-limiting examples of a silicone gum blend are cyclopentasiloxaneand dimethiconol, and cyclotetrasiloxane and cyclopentasiloxane anddimethiconol. The cyclopentasiloxane and dimethiconol blends areavailable, for example, from KCC as SF9902E™ or from Momentive asSilsoft 1215 Dimethicone™. The amount of the silicone gum blend in thecomposition may be in a range from about 0.5% (w/w) to about 2.5% (w/w).

The gelling agent increases the aqueous phase viscosity when introducedin said aqueous phase. Without being bound to any mechanism of action,the topical composition in form of a gel comprises pharmaceutical agentsprimordially dissolved in the aqueous phase of the emulsion, finelydispersed in the continuous jelly phase and the silicone resin,primordially dissolved in the volatile solvent and finely dispersed inthe aqueous phase of the emulsion, dispersed in the continuous jellyphase of the topical composition.

The gelling agent useful in a topical composition of the presentinvention may comprise hydroxypropyl cellulose, hydroxyethyl cellulose,hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose,carboxymethyl cellulose, carbomer, carbomer copolymers, gelatin,aluminum monostearate, dextrin, sodium alginate, alginic acid, pectin,acacia, alginic acid, carrageenan, xanthan, tragacanth, magnesiumaluminum silicate (Veegum®), bentonite, poloxamers (Pluronics®),polyvinyl alcohol, or mixtures thereof. Each possibility is a separateembodiment of the invention. Suitable gelling agents are cellulosederivatives. According to one embodiment, the gelling agent ishydropropyl methylcellulose. According to some embodiments, the gellingagent is not soluble is the volatile solvent and/or in the silicone oilphase of the emulsion. The amount of the gelling agent in thecomposition may be in a range from about 0.05% (w/w) to about 5% (w/w).

According to some embodiments, the pH is maintained in the range fromabout 3.5 to about 5, or from about 4.0 to about 4.6, or from about 4.2to about 4.4 using an appropriate buffering system. The non-limitingexamples of the weak acids suitable for buffering the compositions ofthe present invention include citric acid, citric acid monohydrate,boric acid, and phosphoric acid. Examples of some acid salts which canbe used in the buffering systems of the compositions of the presentinvention include, but are not limited to, sodium citrate, sodiumcitrate dihydrate, monopotassium phosphate, and disodium phosphate.

Upon application of a topical composition to the genital or anorectalarea, the volatile solvent and water evaporate, leaving an adhered, dryfilm which includes at least one pharmaceutically active agent. Thedried film is elastic and durable. It is to be appreciated that thecompositions of the present invention are devoid of polar solventsrequired for dissolving active ingredients, thus providing non-stingingtopical compositions that have a comfortable feel when applying on theanorectal or genital surface.

The emulsions of the instant invention possess the advantage of reducedstinging effect in comparison with non-aqueous or polar compositions.

In an embodiment, the compositions of the instant invention areessentially non-stinging.

In an embodiment, the compositions of the present invention are devoidof acrylates. The adhesiveness of the compositions does not requireacrylates.

Pharmaceutical Agents

The compositions of the present invention further comprise at least onepharmaceutically active agent, such as an anesthetic agent, avasoconstrictor, an antipruritic agent, an anti-inflammatory agent, amuscle relaxant, an astringent, a keratolytic agent, an immunomodulator,a cytotoxin, an antibiotic agent, an antiseptic agent, an anti-acneagent or a combination thereof. Each possibility is a separateembodiment of the invention. Additional pharmaceutical active agentsinclude for example, analgesics, antimicrobial agents and botanicalproducts or extracts. The compositions of the present invention mayfurther comprise antioxidants. The compositions may further contain oneor more protectant active ingredients, excipients and carriers.Pharmaceutically and dermatologically acceptable excipients and carriersas are known in the art may be included in the composition, inparticular for maintaining the stability and sterility of thecomposition, and for promoting delivery, release and/or application ofthe active agent(s) to the body surface to which the composition isapplied.

It is to be understood that the compositions may contain more than oneactive agent, and/or may be suitable for use in treating differentanorectal or genital disorders. The pharmaceutically active agent andthe dosage thereof is dependent upon, for example, the particularcondition to be treated and the age of the subject. In an exemplifiedembodiment, the composition comprises an anesthetic agent and avasoconstrictor. Anesthetic agents include, but are not limited to,pramoxine, procaine, lidocaine, tetracaine, dibucaine, prilocaine,phenacaine, benzyl alcohol, benzocaine, diperodon, dyclonine,dimethisoquin and combinations thereof. Exemplary anesthetic agent ispramoxine. Pharmaceutically acceptable salts of the aforementionedanesthetic agents may also be included in the composition of theinvention. Suitable amounts of such anesthetic agents in the compositionmay be readily ascertained by one of ordinary skill in the art, and mayrange, for example, from about 0.15% (w/w) to about 25% (w/w). In aparticular embodiment, the anesthetic agent is pramoxine HCl orlidocaine. In a particular embodiment, the composition of the inventioncomprises pramoxine HCl at a concentration of 1% w/w based on the totalweight of the composition.

Vasoconstrictors which are suitable for use in the invention includeamphetamines, antihistamines, methylphenidate, mephedrone,oxymetazoline, phenylephrine, pseudoephedrine, psilocybin, phenylephrinehydrochloride, ephedrine sulphate, epinephrine, epinephrinehydrochloride, tetrahydrozoline hydrochloride, and combinations thereof.Suitable amounts of such vasoconstrictor agents in the composition maybe readily ascertained by one of ordinary skill in the art, and mayrange, for example, from about 0.005% (w/w) to about 2.0% (w/w).Exemplary vasoconstrictor agent is phenylephrine HCl. In a particularembodiment, the composition of the invention comprises phenylephrine HClat a concentration of about 0.25% (w/w) based on the total weight of thecomposition.

Antipruritic agents which are suitable for use in the invention includecorticosteroids, camphor, juniper tar and menthol. The non-limitingexamples of corticosteroids include hydrocortisone, fluocinolone,flurandrenolide, triamcinolone, fluticasone, and desonide. Antipruriticagents may further comprise corticosteroids such as tetrahydrocortisol,prednisone; prednisolone, fludrocortisone, 11-desoxycortisol, cortisone,corticosterone, paramethasone, betamethasone, dexamethasone,desoxycorticosterone acetate, desoxycorticosterone pivalate,fludrocortisone acetate, cortisol acetate, cortisol cypionate, cortisolsodium phosphate, cortisol sodium succinate, beclopmethasonedipropionate, betamethasone, betamethasone sodium phosphate and acetate,betamethasone dipropionate, betamethasone valerate, betamethasonebenzoate, cortisone acetate, dexamethasone, dexamethasone sodiumphosphate, dexamethasone acetate, fuprednisolone, meprednisone,methylprednisolone, methylprednisolone acetate, methylprednisolonesodium succinate, paramethasone acetate, prednisolone, prednisoloneacetate, prednisolone sodium phosphate, prednisolone sodium succinate,prednisolone tebutate, prednisone, triamcinolone acetonide,triamcinolone diacetate, triamcinolone hexacotonide, desoximetasone,flumethasone pivalate, fluocinolone acetonide, fluocinonide,fluorometholone, halcinonide, and medrysone. Suitable amounts ofantipruritic agents in the composition may be readily ascertained by oneof ordinary skill in the art, and may range, for example, from about0.1% (w/w) to about 5.0% (w/w).

Anti-inflammatory agents include salicylic acid, indomethacin, sodiumindomethacin trihydrate, salicylamide, naproxen, colchicine, fenoprofen,sulindac, diflunisal, diclofenac, indoprofen and sodium salicylamide.

Muscle relaxants which are suitable for use in the invention includenitroglycerin, nifedipine, dilatiazem, verapamil, amlodopine,sildenafil, tizanidine, and baclofen, or salts thereof including, butnot limited to, sildenafil citrate. Suitable amounts of such musclerelaxants in the composition may be readily ascertained by one ofordinary skill in the art, and may range, for example, from about 0.1%(w/w) to about 15% (w/w).

Anti-acne agents are selected from the group comprising adapalene,benzoyl peroxide, tazarotene, azelaic acid, and clindamycin.

A topical composition of the present invention may further include anastringent. As used herein, an “astringent” refers to a substance thatcauses tissue (e.g., a hemorrhoidal) to contract and can optionallyarrest secretion or control bleeding from tissue. Astringents which aresuitable for use in the invention include, e.g., alum, tannic acid,calamine, witch hazel, zinc oxide, or a combination thereof. Suitableamounts of such astringents in the composition may be readilyascertained by one of ordinary skill in the art, and may range, forexample, from about 2.0% (w/w) to about 50% (w/w).

A topical composition of the present invention may further include akeratolytic agent. As used herein, a “keratolytic agent” refers to asubstance that causes desquamation (loosening) and debridement orsloughing of the surface cells of the epidermis. The keratolytic agentused in the compositions of the present invention are typicallypharmaceutically acceptable for topical use in humans. Suitablekeratolytic agents include, but are not limited to, alcloxa, resorcinol,or a combination thereof. Suitable amounts of such keratolytic agents inthe composition may be readily ascertained by one of ordinary skill inthe art, and may range, for example, from about 0.1% (w/w) to about 5%(w/w).

Antibiotics for use in the invention are typically those suitable fortopical application. The antibiotic(s) may be classified in one or moreof the following groups: penicillins, cephalosporins, carbepenems,beta-lactam antibiotics, aminoglycosides, amphenicols, ansamycins,macrolides, lincosamides, glycopeptides, polypeptides, tetracylines,chloramphenicol, quinolones, fucidins, sulfonamides, sulfones,nitrofurans, diaminopyrimidines, trimethoprims, rifamycins, oxalines,streptogramins, lipopeptides, ketolides, polyenes, azoles, andechinocandins.

Specific examples of antibiotics which are suitable for use in theinvention include: amikacin, aminosidine, paromomycin, chloramphenicol,ciprofloxacin, clindamycin, coli stimethate-sodium, colistin,enfuvirtid, enoxacin, erythromycin, flucloxacillin, fosfomycin,fusafungin, gentamicin, levofloxacin, linezolid, mefloquin,metronidazol, mezlocillin, moxifloxacin, mupirocin, norfloxacin,ofloxacin, oxacillin, penicillin G, penicillin V,phenoxymethylpenicillin, phenoxymethylpenicillin-benzathin, pipemidinicacid, piperacillin, piperacillin+tazobactam, proguanil, propicillin,pyrimethamine, retapamulin, rifaximin, roxithromycin, sodiumsulfacetamide, sulbactam, sulbactam+ampicillin, sulfadiazine,spiramycin, sultamicillin, tazobactam+piperacillin, teicoplanin,telithromycin, tigecyclin, vancomycin and combinations thereof.

Antiseptics which are suitable for use in the invention include, e.g.,triclosan, phenoxy isopropanol, chlorhexidine gluconate, povidoneiodine, and any combination thereof.

Antioxidative compounds may also be included in the composition, inparticular the antioxidative compounds collectively termed catechins.These include for example, epicatechin, epicatechin gallate,epigallocatechin gallate, and gallocatechin, as well as stereoisomersand enantiomers of these compounds and combinations thereof. Suchcompounds may be provided as synthetic compounds or in the forms ofmixtures as components of plant extracts, in particular green teaextracts. Botanical products and extracts include those derived frompeppermint, ginger horseradish, yarrow, chamomile, rosemary, capsicum,aloe vera, tea tree oil (melaleuca oil), among many others.

A topical composition of the present invention may further includeprotectant active ingredients. The protectant active ingredients can beselected from the group consisting of aluminum hydroxide gel, cocoabutter, aqueous solution of glycerin, hard fat, kaolin, lanolin, mineraloil, petrolatum, topical starch, white petrolatum, cod liver, sharkliver oil, and a combination thereof. The protectant active ingredientand the dosage thereof is dependent upon, for example, the particularcondition to be treated and the pharmaceutical active agents present inthe composition.

A topical composition of the present invention may include one or moreof the following additional ingredients: emulsifiers (e.g. anionic,cationic or nonionic), chelating agents, colorants, emollients,fragrances, humectants, lubricants, moisturizers, preservatives, skinpenetration enhancers, stabilizers, thickeners, and viscosity modifiers.

Formulations

According to an embodiment, a topical composition of the presentinvention comprises: trimethylsiloxysilicate; at least one surfactantselected from the group consisting of sodium lauryl sulfate, alkyl- andalkoxy-dimethicone copolyol, polysorbate and a combination thereof; anon-polar volatile siloxane solvent, at least 15% (w/w) water, and apharmaceutical agent selected from the group consisting of pramoxine,phenylephrine, hydrocortisone, salicylic acid, nitroglycerine,sildenafil, or their salts and combinations thereof. In an embodiment,the water is present in the composition from about 15% (w/w) to about40% (w/w). In an embodiment, the water is part of a buffer to adjust thepH of the composition to a pH of about 4.2-4.4. In an embodiment, thecomposition further comprises a viscosity modifier.

According to an embodiment, a topical composition of the presentinvention comprises: from about 10.0% (w/w) to about 30.0% (w/w) oftrimethylsiloxysilicate; from about 1.0% (w/w) to about 5.0% (w/w) of atleast one surfactant selected from the group consisting of sodium laurylsulfate, alkyl- and alkoxy-dimethicone copolyol, polysorbate and acombination thereof; from about 30.0% (w/w) to about 75.0% (w/w) of anon-polar volatile siloxane solvent, at least 15% (w/w) water, and fromabout 0.005% (w/w) to about 25.0% (w/w) of a pharmaceutical agentselected from the group consisting of pramoxine, phenylephrine,hydrocortisone, salicylic acid, nitroglycerine, sildenafil, or theirsalts and combinations thereof. In an embodiment, the water is presentin the composition from about 15% (w/w) to about 40% (w/w). In anembodiment, the composition further comprises a buffer to adjust the pHof the composition to a pH of about 4.2-4.4. In an embodiment, thecomposition further comprises a viscosity modifier.

According to an embodiment, a topical composition of the presentinvention comprises: (i) a silicone resin film forming agent comprisingsiloxysilicate, silsesquioxane, or a derivative or a combinationthereof; (ii) an anionic surfactant; (iii) a volatile solvent, (iv)water; and (v) at least one pharmaceutical agent.

According to an embodiment, a topical composition of the presentinvention comprises: (i) a silicone resin film forming agent comprisingsiloxysilicate, silsesquioxane, or a derivative or a combinationthereof; (ii) an anionic surfactant; (iii) a nonionic surfactant, (iv) avolatile solvent, (v) water; and (vi) at least one pharmaceutical agent.

According to an embodiment, a topical composition of the presentinvention comprises: (i) a silicone resin film forming agent comprisingsiloxysilicate, silsesquioxane, or a derivative or a combinationthereof; (ii) a nonionic surfactant; (iii) a volatile solvent, (iv)water; and (v) at least one pharmaceutical agent.

According to an embodiment, a topical composition of the presentinvention comprises: (i) a silicone resin film forming agent comprisingsiloxysilicate, silsesquioxane, or a derivative or a combinationthereof; (ii) an anionic surfactant; (iii) a volatile solvent, (iv)water; (v) gelling agent; and (vi) at least one pharmaceutical agent.

According to an embodiment, a topical composition of the presentinvention comprises: (i) a silicone resin film forming agent comprisingsiloxysilicate, silsesquioxane, or a derivative or a combinationthereof; (ii) an anionic surfactant; (iii) a nonionic surfactant, (iv) avolatile solvent, (v) water; (vi) gelling agent; and (vii) at least onepharmaceutical agent.

According to an embodiment, a topical composition of the presentinvention comprises: (i) a silicone resin film forming agent comprisingsiloxysilicate, silsesquioxane, or a derivative or a combinationthereof; (ii) a nonionic surfactant; (iii) a volatile solvent, (iv)water; (v) gelling agent; and (vi) at least one pharmaceutical agent.

According to an embodiment, a topical composition of the presentinvention comprises: (i) trimethylsiloxysilicate; (ii) sodium alkylsulfate; (iii) a volatile solvent, selected from the group consisting ofmethylsiloxane, a polydimethylsiloxane, aliphatic hydrocarbon and acombination thereof; (iv) water; and (v) at least one pharmaceuticalagent.

According to an embodiment, a topical composition of the presentinvention comprises: (i) trimethylsiloxysilicate; (ii) sodium laurylsulfate; (iii) a volatile solvent, selected from the group consisting ofmethylsiloxane, hexamethyldisiloxane, isooctane and a combinationthereof; (iv) water; and (v) at least one pharmaceutical agent.

According to an embodiment, a topical composition of the presentinvention comprises: (i) trimethylsiloxysilicate; (ii) sodium alkylsulfate; (iii) alkyl- and alkoxy-dimethicone copolyol; (iv) a volatilesolvent, selected from the group consisting of methylsiloxane, apolydimethylsiloxane, aliphatic hydrocarbon and a combination thereof;(v) water; and (vi) at least one pharmaceutical agent.

According to an embodiment, a topical composition of the presentinvention comprises: (i) trimethylsiloxysilicate; (ii) sodium laurylsulfate; (iii) Cetyl PEG/PPG-10/1 Dimethicone; (iv) a volatile solvent,selected from the group consisting of methylsiloxane,hexamethyldisiloxane, isooctane and a combination thereof; (v) water;and (vi) at least one pharmaceutical agent.

According to an embodiment, a topical composition of the presentinvention comprises: (i) trimethylsiloxysilicate; (ii) polysorbate;(iii) alkyl- and alkoxy-dimethicone copolyol; (iv) a volatile solvent,selected from the group consisting of methylsiloxane,polydimethylsiloxane, aliphatic hydrocarbon and a combination thereof;(v) water; and (vi) at least one pharmaceutical agent.

According to an embodiment, a topical composition of the presentinvention comprises: (i) trimethylsiloxysilicate; (ii) Tween 80; (iii)Cetyl PEG/PPG-10/1 Dimethicone; (iv) a volatile solvent, selected fromthe group consisting of methylsiloxane, hexamethyldisiloxane, isooctaneand a combination thereof; (v) water; and (vi) at least onepharmaceutical agent.

According to an embodiment, a topical composition of the presentinvention comprises: (i) trimethylsiloxysilicate; (ii) sodium alkylsulfate; (iii) a volatile solvent, selected from the group consisting ofmethylsiloxane, a polydimethylsiloxane, aliphatic hydrocarbon and acombination thereof; (iv) water; (v) cellulose derivatives at least onepharmaceutical agent.

According to an embodiment, a topical composition of the presentinvention comprises: (i) trimethylsiloxysilicate; (ii) sodium laurylsulfate; (iii) a volatile solvent, selected from the group consisting ofmethylsiloxane, hexamethyldisiloxane, isooctane and a combinationthereof; (iv) water; (v) hydroxypropyl methyl cellulose; and (vi) atleast one pharmaceutical agent.

According to an embodiment, a topical composition of the presentinvention comprises: (i) a silicone resin film forming agent comprisingsiloxysilicate, silsesquioxane, or a derivative or a combinationthereof; (ii) a surfactant; (iii) a volatile solvent, (iv) water; (v) atleast one pharmaceutical agent; (vi) a dimethicone/vinyldimethiconecrosspolymer; and (vii) a silicone gum blend.

According to an embodiment, a topical composition of the presentinvention comprises: (i) a silicone resin film forming agent comprisingsiloxysilicate, silsesquioxane, or a derivative or a combinationthereof; (ii) a surfactant; (iii) a volatile solvent, (iv) water; (v) atleast one pharmaceutical agent; (vi) a dimethicone/vinyldimethiconecrosspolymer; (vii) a silicone gum blend; and (ix) a gelling agent.

According to an embodiment, a topical composition of the presentinvention comprises: (i) a silicone resin film forming agent comprisingsiloxysilicate, silsesquioxane, or a derivative or a combinationthereof; (ii) anionic surfactant; (iii) a volatile solvent, (iv) water;(v) at least one pharmaceutical agent; (vi) adimethicone/vinyldimethicone crosspolymer; and (vii) a silicone gumblend.

According to an embodiment, a topical composition of the presentinvention comprises: (i) a silicone resin film forming agent comprisingsiloxysilicate, silsesquioxane, or a derivative or a combinationthereof; (ii) anionic surfactant; (iii) a volatile solvent, (iv) water;(v) at least one pharmaceutical agent; (vi) adimethicone/vinyldimethicone crosspolymer; (vii) a silicone gum blend;and (ix) a gelling agent.

According to an embodiment, a topical composition of the presentinvention comprises: (i) a silicone resin film forming agent; (ii)anionic surfactant; (iii) nonionic surfactant; (iv) a volatile solvent,(v) water; (vi) at least one pharmaceutical agent; (vii) adimethicone/vinyldimethicone crosspolymer; and (viii) a silicone gumblend.

According to an embodiment, a topical composition of the presentinvention comprises: (i) a silicone resin film forming agent comprisingsiloxysilicate, silsesquioxane, or a derivative or a combinationthereof; (ii) anionic surfactant; (Iii) nonionic surfactant; (iv) avolatile solvent, (v) water; (vi) at least one pharmaceutical agent;(vii) a dimethicone/vinyldimethicone crosspolymer; (viii) a silicone gumblend; and (ix) a gelling agent.

According to an embodiment, a topical composition of the presentinvention comprises: (i) a silicone resin film forming agent comprisingsiloxysilicate, silsesquioxane, or a derivative or a combinationthereof; (ii) nonionic surfactant; (iii) a volatile solvent, (iv) water;(v) at least one pharmaceutical agent; (vi) adimethicone/vinyldimethicone crosspolymer; and (vii) a silicone gumblend.

According to an embodiment, a topical composition of the presentinvention comprises: (i) a silicone resin film forming agent comprisingsiloxysilicate, silsesquioxane, or a derivative or a combinationthereof; (ii) nonionic surfactant; (iii) a volatile solvent, (iv) water;(v) at least one pharmaceutical agent; (vi) adimethicone/vinyldimethicone crosspolymer; (vii) a silicone gum blend;and (ix) a gelling agent.

According to an embodiment, a topical composition of the presentinvention comprises: (i) trimethylsiloxysilicate; (ii) sodium alkylsulfate; (iii) a volatile solvent, selected from the group consisting ofmethylsiloxane, a polydimethylsiloxane, aliphatic hydrocarbon and acombination thereof; (iv) water; (v) at least one pharmaceutical agent;(vi) bis-vinyldimethicone, vinyldimethicone and hydrogen dimethicone;and (vii) dimethiconol and silicone oil blend.

According to an embodiment, a topical composition of the presentinvention comprises: (i) trimethylsiloxysilicate; (ii) sodium alkylsulfate; (iii) a volatile solvent, selected from the group consisting ofmethylsiloxane, a polydimethylsiloxane, aliphatic hydrocarbon and acombination thereof; (iv) water; (v) at least one pharmaceutical agent;(vi) bis-vinyldimethicone, vinyldimethicone and hydrogen dimethicone;(vii) dimethiconol and silicone oil blend; and (iv) cellulosederivative.

According to an embodiment, a topical composition of the presentinvention comprises: (i) trimethylsiloxysilicate; (ii) sodium alkylsulfate; (iii) alkyl- and alkoxy-dimethicone copolyol; (iv) a volatilesolvent, selected from the group consisting of methylsiloxane, apolydimethylsiloxane, aliphatic hydrocarbon and a combination thereof;(v) water; (vi) at least one pharmaceutical agent; (vii)bis-vinyldimethicone, vinyldimethicone and hydrogen dimethicone; and(viii) dimethiconol and silicone oil blend.

According to an embodiment, a topical composition of the presentinvention comprises: (i) trimethylsiloxysilicate; (ii) sodium alkylsulfate; (iii) alkyl- and alkoxy-dimethicone copolyol; (iv) a volatilesolvent, selected from the group consisting of methylsiloxane, apolydimethylsiloxane, aliphatic hydrocarbon and a combination thereof;(v) water; (vi) at least one pharmaceutical agent; (vii)bis-vinyldimethicone, vinyldimethicone and hydrogen dimethicone; (viii)dimethiconol and silicone oil blend; and (ix) cellulose derivative.

According to an embodiment, a topical composition of the presentinvention comprises: (i) trimethylsiloxysilicate; (ii) polysorbate;(iii) alkyl- and alkoxy-dimethicone copolyol; (iv) a volatile solvent,selected from the group consisting of methylsiloxane, apolydimethylsiloxane, aliphatic hydrocarbon and a combination thereof;(v) water; (vi) at least one pharmaceutical agent; (vii)bis-vinyldimethicone, vinyldimethicone and hydrogen dimethicone; and(viii) dimethiconol and silicone oil blend.

According to an embodiment, a topical composition of the presentinvention comprises: (i) trimethylsiloxysilicate; (ii) polysorbate;(iii) alkyl- and alkoxy-dimethicone copolyol; (iv) a volatile solvent,selected from the group consisting of methylsiloxane, apolydimethylsiloxane, aliphatic hydrocarbon and a combination thereof;(v) water; (vi) at least one pharmaceutical agent; (vii)bis-vinyldimethicone, vinyldimethicone and hydrogen dimethicone; (viii)dimethiconol and silicone oil blend; and (ix) cellulose derivative.

According to an embodiment, a topical composition of the presentinvention comprises: (i) trimethylsiloxysilicate; (ii) sodium laurylsulfate; (iii) a volatile solvent, selected from the group consisting ofmethylsiloxane, hexamethyldisiloxane, isooctane and a combinationthereof; (iv) water; (v) at least one pharmaceutical agent, selectedfrom the group consisting of an anesthetic agent, a vasoconstrictor, anantipruritic agent, an immunomodulator, a cytotoxin, ananti-inflammatory agent, a muscle relaxant, and a combination thereof;(vi) bis-vinyldimethicone, vinyldimethicone and hydrogen dimethicone;and (vii) cyclopentasiloxane and dimethiconol.

According to an embodiment, a topical composition of the presentinvention comprises: (i) trimethylsiloxysilicate; (ii) sodium laurylsulfate; (iii) a volatile solvent, selected from the group consisting ofmethylsiloxane, hexamethyldisiloxane, isooctane and a combinationthereof; (iv) water; (v) at least one pharmaceutical agent, selectedfrom the group consisting of an anesthetic agent, a vasoconstrictor, anantipruritic agent, an immunomodulator, a cytotoxin, ananti-inflammatory agent, a muscle relaxant, and a combination thereof;(vi) bis-vinyldimethicone, vinyldimethicone and hydrogen dimethicone;(vii) cyclopentasiloxane and dimethiconol; and (iv) hydroxypropyl methylcellulose.

According to an embodiment, a topical composition of the presentinvention comprises: (i) trimethylsiloxysilicate; (ii) sodium laurylsulfate; (iii) Cetyl PECK/PPCA-10/1 Dimethicone; (iv) a volatilesolvent, selected from the group consisting of methylsiloxane,hexamethyldisiloxane, isooctane and a combination thereof; (v) water;(vi) at least one pharmaceutical agent selected from the groupconsisting of an anesthetic agent, a vasoconstrictor, an antipruriticagent, an anti-inflammatory agent, a muscle relaxant, or a combinationthereof; (vii) bis-vinyldimethicone, vinyldimethicone and hydrogendimethicone; and (viii) cyclopentasiloxane and dimethiconol.

According to an embodiment, a topical composition of the presentinvention comprises: (i) trimethylsiloxysilicate; (ii) sodium laurylsulfate; (iii) Cetyl PEG/PPG-10/1 Dimethicone; (iv) a volatile solvent,selected from the group consisting of hexamethyldisiloxane, isooctaneand a combination thereof; (v) water; (vi) at least one pharmaceuticalagent selected from the group consisting of an anesthetic agent, avasoconstrictor, an immunomodulator, a cytotoxin, an antipruritic agent,an anti-inflammatory agent, a muscle relaxant, or a combination thereof;(vii) bis-vinyldimethicone, vinyldimethicone and hydrogen dimethicone;(viii) cyclopentasiloxane and dimethiconol; and (ix) hydroxypropylmethyl cellulose.

According to an embodiment, a topical composition of the presentinvention comprises: (i) trimethylsiloxysilicate; (ii) Tween 80; (iii)Cetyl PEG/PPG-10/1 Dimethicone; (iv) a volatile solvent, selected fromthe group consisting of methylsiloxane, hexamethyldisiloxane, isooctaneand a combination thereof; (v) water; (vi) at least one pharmaceuticalagent selected from the group consisting of an anesthetic agent, avasoconstrictor, an antipruritic agent, an anti-inflammatory agent, amuscle relaxant, an immunomodulator, a cytotoxin, or a combinationthereof; (vii) bis-vinyldimethicone, vinyldimethicone and hydrogendimethicone; and (viii) cyclopentasiloxane and dimethiconol.

According to an embodiment, a topical composition of the presentinvention comprises: (i) trimethylsiloxysilicate; (ii) Tween 80; (iii)Cetyl PEG/PPG-10/1 Dimethicone; (iv) a volatile solvent, selected fromthe group consisting of methylsiloxane, hexamethyldisiloxane, isooctaneand a combination thereof; (v) water; (vi) at least one pharmaceuticalagent selected from the group consisting of an anesthetic agent, avasoconstrictor, an antipruritic agent, an anti-inflammatory agent, amuscle relaxant, an immunomodulator, a cytotoxin, or a combinationthereof; (vii) bis-vinyldimethicone, vinyldimethicone and hydrogendimethicone; (viii) cyclopentasiloxane and dimethiconol; and (ix)hydroxypropyl methyl cellulose.

According to an embodiment, a topical composition of the presentinvention comprises: (i) about 10-40% (w/w) of a silicone resin filmforming agent comprising siloxysilicate, silsesquioxane, or a derivativeor a combination thereof; (ii) about 0.5% (w/w) to about 7% (w/w) of asurfactant; (iii) about 30% (w/w) to about 80% (w/w) of a volatilesolvent; (iv) about 20% (w/w) to about 40% (w/w) of water; and (v) about0.005% (w/w) to about 25% (w/w) of at least one pharmaceutical agent.

According to an embodiment, a topical composition of the presentinvention comprises: (i) about 10% (w/w) to about 40% (w/w) of asilicone resin film forming agent comprising siloxysilicate,silsesquioxane, or a derivative or a combination thereof; (ii) about0.5% (w/w) to about 2.5% (w/w) of an anionic surfactant; (iii) about 30%(w/w) to about 80% (w/w) of a volatile solvent; (iv) about 15$ (w/w) toabout 40% (w/w) of water; and (v) about 0.005% (w/w) to about 25% (w/w)of at least one pharmaceutical agent.

According to an embodiment, a topical composition of the presentinvention comprises: (i) about 10% (w/w) to about 40% (w/w) of asilicone resin film forming agent comprising siloxysilicate,silsesquioxane, or a derivative or a combination thereof; (ii) about0.5% (w/w) to about 2.5% (w/w) of an anionic surfactant; (iii) about 30%(w/w) to about 80% (w/w) of a volatile solvent; (iv) about 20% (w/w) toabout 40% (w/w) of water; (v) about 0.005% (w/w) to about 25% (w/w) ofat least one pharmaceutical agent; and (vi) about 0.05% (w/w) to about5.0% (w/w) gelling agent.

According to an embodiment, a topical composition of the presentinvention comprises: (i) about 10% (w/w) to about 40% (w/w) of asilicone resin film forming agent comprising siloxysilicate,silsesquioxane, or a derivative or a combination thereof; (ii) about0.5% (w/w) to about 2.5% (w/w) of an anionic surfactant; (iii) about 2%(w/w) to about 7% (w/w) of a nonionic surfactant; (iv) about 30% (w/w)to about 50% (w/w) of a volatile solvent; (v) about 25% (w/w) to about40% (w/w) of water; and (vi) about 0.005% (w/w) to about 25% (w/w) of atleast one pharmaceutical agent.

According to an embodiment, a topical composition of the presentinvention comprises: (i) about 10% (w/w) to about 40% (w/w) of asilicone resin film forming agent comprising siloxysilicate,silsesquioxane, or a derivative or a combination thereof; (ii) about0.5% (w/w) to about 2.5% (w/w) of an anionic surfactant; (iii) about 2%(w/w) to about 7% (w/w) of a nonionic surfactant; (iv) about 30% (w/w)to about 80% (w/w) of a volatile solvent; (v) about 20% (w/w) to about40% (w/w) of water; (vi) about 0.005% (w/w) to about 25% (w/w) of atleast one pharmaceutical agent and (vii) about 0.05% (w/w) to about 5.0%(w/w) gelling agent.

According to an embodiment, a topical composition of the presentinvention comprises: (i) about 10$ (w/w) to about 40% (w/w) of asilicone resin film forming agent comprising siloxysilicate,silsesquioxane, or a derivative or a combination thereof; (ii) about0.5% (w/w) to about 7.0% (w/w) of a nonionic surfactant; (iii) about 30%(w/w) to about 80% (w/w) of a volatile solvent; (iv) about 20% (w/w) toabout 40% (w/w) of water; and (v) about 0.005% (w/w) to about 25% (w/w)of at least one pharmaceutical agent.

According to an embodiment, a topical composition of the presentinvention comprises: (i) about 10% (w/w) to about 40% (w/w) of asilicone resin film forming agent comprising siloxysilicate,silsesquioxane, or a derivative or a combination thereof; (ii) about0.5% (w/w) to about 7.0% (w/w) of a nonionic surfactant; (iii) about 30%(w/w) to about 80% (w/w) of a volatile solvent; (iv) about 20% (w/w) toabout 40% (w/w) of water; (v) about 0.005% (w/w) to about 25% (w/w) ofat least one pharmaceutical agent; and (vi) about 0.05% (w/w) to about5% (w/w) gelling agent.

According to an embodiment, a topical composition of the presentinvention comprises: (i) about 10% (w/w) to about 40% (w/w) oftrimethylsiloxysilicate; (ii) about 0.5% (w/w) to about 2.5% (w/w) ofsodium alkyl sulfate; (iii) about 30% (w/w) to about 80% (w/w) of avolatile solvent, selected from the group consisting of methylsiloxane,a polydimethylsiloxane, aliphatic hydrocarbon and a combination thereof;(iv) about 15% (w/w) to about 40% (w/w) of water; (v) about 0.005% (w/w)to about 25% (w/w) of at least one pharmaceutical agent, selected fromthe group consisting of an anesthetic agent, a vasoconstrictor, anantipruritic agent, an anti-inflammatory agent, a muscle relaxant, or acombination thereof; (vi) about 5.0% (w/w) to about 15% (w/w)bis-vinyldimethicone, vinyldimethicone and hydrogen dimethicone; and(vii) about 0.5% (w/w) to about 2.5% (w/w) dimethiconol and silicone oilblend.

According to an embodiment, a topical composition of the presentinvention comprises: (i) about 10% (w/w) to about 40% (w/w) oftrimethylsiloxysilicate; (ii) about 0.5% (w/w) to about 2.5% (w/w) ofsodium alkyl sulfate; (iii) about 30% (w/w) to about 80% (w/w) of avolatile solvent, selected from the group consisting of methylsiloxane,a polydimethylsiloxane, aliphatic hydrocarbon and a combination thereof;(iv) about 15% (w/w) to about 40% (w/w) of water; (v) about 0.005% (w/w)to about 25% (w/w) of at least one pharmaceutical agent, selected fromthe group consisting of an anesthetic agent, a vasoconstrictor, anantipruritic agent, an anti-inflammatory agent, a muscle relaxant, or acombination thereof; (vi) about 5.0% (w/w) to about 15% (w/w)bis-vinyldimethicone, vinyldimethicone and hydrogen dimethicone; (vii)about 0.5% (w/w) to about 2.5% (w/w) dimethiconol and silicone oilblend; and (viii) about 0.05% (w/w) to about 5.0% (w/w) cellulosederivative.

According to an embodiment, a topical composition of the presentinvention comprises: (i) about 10% (w/w) to about 40% (w/w) oftrimethylsiloxysilicate; (ii) about 0.5% (w/w) to about 2.5% (w/w) ofsodium alkyl sulfate; (iii) about 2.0% (w/w) to about 7% (w/w) of alkyl-and alkoxy-dimethicone copolyol; (iv) about 30% (w/w) to about 80% (w/w)of a volatile solvent, selected from the group consisting ofmethylsiloxane, a polydimethylsiloxane, aliphatic hydrocarbon and acombination thereof; (v) about 15% (w/w) to about 40% (w/w) of water;(vi) about 0.005% (w/w) to about 25% (w/w) of at least onepharmaceutical agent, selected from the group consisting of ananesthetic agent, a vasoconstrictor, an antipruritic agent, ananti-inflammatory agent, a muscle relaxant, or a combination thereof;(vii) about 5.0% (w/w) to about 15% (w/w) bis-vinyldimethicone,vinyldimethicone and hydrogen dimethicone; and (viii) about 0.5% (w/w)to about 2.5% (w/w) dimethiconol and silicone oil blend.

According to an embodiment, a topical composition of the presentinvention comprises: (i) about 10% (w/w) to about 40% (w/w) oftrimethylsiloxysilicate; (ii) about 0.5% (w/w) to about 2.5% (w/w) ofsodium alkyl sulfate; (iii) about 2.0% (w/w) to about 7% (w/w) of alkyl-and alkoxy-dimethicone copolyol; (iv) about 30% (w/w) to about 80% (w/w)of a volatile solvent, selected from the group consisting ofmethylsiloxane, a polydimethylsiloxane, aliphatic hydrocarbon and acombination thereof; (v) about 15% (w/w) to about 40% (w/w) of water;(vi) about 0.005% (w/w) to about 25% (w/w) of at least onepharmaceutical agent, selected from the group consisting of ananesthetic agent, a vasoconstrictor, an antipruritic agent, ananti-inflammatory agent, a muscle relaxant, or a combination thereof;(vii) about 5.0% (w/w) to about 15% (w/w) bis-vinyldimethicone,vinyldimethicone and hydrogen dimethicone; (viii) about 0.5% (w/w) toabout 2.5% (w/w) dimethiconol and silicone oil blend and (viii) about0.05% (w/w) to about 5% (w/w) cellulose derivative.

According to an embodiment, a topical composition of the presentinvention comprises: (i) about 10% (w/w) to about 40% (w/w) oftrimethylsiloxysilicate; (ii) about 0.5% (w/w) to about 2.5% (w/w) ofpolysorbate; (iii) about 2.0% (w/w) to about 7% (w/w) of alkyl- andalkoxy-dimethicone copolyol; (iv) about 30% (w/w) to about 80% (w/w) ofa volatile solvent, selected from the group consisting ofmethylsiloxane, a polydimethylsiloxane, aliphatic hydrocarbon and acombination thereof; (v) about 15% (w/w) to about 40% (w/w) of water;(vi) about 0.005% (w/w) to about 25% (w/w) of at least onepharmaceutical agent, selected from the group consisting of ananesthetic agent, a vasoconstrictor, an antipruritic agent, animmunomodulator, a muscle relaxant, or a combination thereof; (vii)about 5.0% (w/w) to about 15% (w/w) bis-vinyldimethicone,vinyldimethicone and hydrogen dimethicone; and (viii) about 0.5% (w/w)to about 2.5% (w/w) dimethiconol and silicone oil blend.

According to an embodiment, a topical composition of the presentinvention comprises: (i) about 10% (w/w) to about 40% (w/w) oftrimethylsiloxysilicate; (ii) about 0.5% (w/w) to about 2.5% (w/w) ofpolysorbate; (iii) about 2.0% (w/w) to about 7.0% (w/w) of alkyl- andalkoxy-dimethicone copolyol; (iv) about 30% (w/w) to about 80% (w/w) ofa volatile solvent, selected from the group consisting ofmethylsiloxane, a polydimethylsiloxane, aliphatic hydrocarbon and acombination thereof; (v) about 15.0% (w/w) to about 40% (w/w) of water;(vi) about 0.005% (w/w) to about 25% (w/w) of at least onepharmaceutical agent, selected from the group consisting of ananesthetic agent, a vasoconstrictor, an antipruritic agent, akeratolytic, a protectant, an anti-inflammatory agent, an astringent, amuscle relaxant, or a combination thereof; (vii) about 5.0% (w/w) toabout 15% (w/w) bis-vinyldimethicone, vinyldimethicone and hydrogendimethicone; (viii) about 0.5% (w/w) to about 2.5% (w/w) dimethiconoland silicone oil blend and (viii) about 0.05% (w/w) to about 5% (w/w)cellulose derivative.

According to an embodiment, a topical composition of the presentinvention comprises: (i) about 15% (w/w) trimethylsiloxysilicate; (ii)about 3% (w/w) sodium lauryl sulfate; (iii) about 22% (w/w)hexamethyldisiloxane and 21% (w/w) isooctane; (iv) about 27% (w/w) wateror citrate buffer or a combination thereof; (v) about 1% (w/w)pramoxine; (vi) about 0.25% (w/w) phenylephrine; (vii) about 5% (w/w)bis-vinyldimethicone and 5% (w/w) vinyldimethicone and hydrogendimethicone; and (viii) about 1% (w/w) cyclopentasiloxane anddimethiconol.

According to an embodiment, a topical composition of the presentinvention comprises: (i) about 15% (w/w) trimethylsiloxysilicate; (ii)about 3% (w/w) sodium lauryl sulfate; (iii) about 22% (w/w)hexamethyldisiloxane and 21% (w/w) isooctane; (iv) about 27% (w/w) wateror citrate buffer or a combination thereof; (v) about 1% (w/w)pramoxine; (vi) about 0.25% (w/w) phenylephrine; (vii) about 5% (w/w)bis-vinyldimethicone and 5% (w/w) vinyldimethicone and hydrogendimethicone; (viii) about 1% (w/w) cyclopentasiloxane and dimethiconol;and (ix) about 0.5% (w/w) hydroxypropyl methyl cellulose.

According to an embodiment, a topical composition of the presentinvention comprises: (i) about 15% (w/w) trimethylsiloxysilicate; (ii)about 1.5% (w/w) sodium lauryl sulfate; (iii) about 4% (w/w) CetylPEG/PPG-10/1 Dimethicone; (iv) about 22% (w/w) hexamethyldisiloxane and21% (w/w) isooctane; (v) about 25% (w/w) water; (vi) about 1% (w/w)pramoxine; (vii) about 0.25% (w/w) phenylephrine; (viii) about 5% (w/w)bis-vinyldimethicone and 5% (w/w) vinyldimethicone and hydrogendimethicone; and (ix) about 1% (w/w) cyclopentasiloxane anddimethiconol.

According to an embodiment, a topical composition of the presentinvention comprises: (i) about 15% (w/w) trimethylsiloxysilicate; (ii)about 1.5% (w/w) sodium lauryl sulfate; (iii) about 4% (w/w) CetylPEG/PPG-10/1 Dimethicone; (iv) about 18% (w/w) hexamethyldisiloxane and19% (w/w) isooctane; (v) about 30% (w/w) water; (vi) about 1% (w/w)pramoxine; (vii) about 0.25% (w/w) phenylephrine; (viii) about 5% (w/w)bis-vinyldimethicone and 5% (w/w) vinyldimethicone and hydrogendimethicone; (ix) about 1% (w/w) cyclopentasiloxane and dimethiconol;and (x) about 0.5% (w/w) hydroxypropyl methyl cellulose.

According to an embodiment, a topical composition of the presentinvention comprises: (i) about 15% (w/w) trimethylsiloxysilicate; (ii)about 1.5% (w/w) Tween 80; (iii) about 4% (w/w) Cetyl PEG/PPG-10/1Dimethicone; (iv) about 22% (w/w) hexamethyldisiloxane and 21% (w/w)isooctane; (v) about 25% (w/w) water; (vi) about 1% (w/w) pramoxine;(vii) about 0.25% (w/w) phenylephrine; (viii) about 5% (w/w)bis-vinyldimethicone and 5% (w/w) vinyldimethicone and hydrogendimethicone; and (ix) about 1% (w/w) cyclopentasiloxane anddimethiconol.

According to an embodiment, a topical composition of the presentinvention comprises: (i) about 15% (w/w) trimethylsiloxysilicate; (ii)about 1.5% (w/w) Tween 80; (iii) about 4% (w/w) Cetyl PECK/EPG-10/1Dimethicone; (iv) about 18% (w/w) hexamethyldisiloxane and 19% (w/w)isooctane; (v) about 30% (w/w) water; (vi) about 1% (w/w) pramoxine;(vii) about 0.25% (w/w) phenylephrine; (viii) about 5% (w/w)bis-vinyldimethicone and 5% (w/w) vinyldimethicone and hydrogendimethicone; (ix) about 1% (w/w) cyclopentasiloxane and dimethiconol;and (x) about 0.5% (w/w) hydroxypropyl methyl cellulose.

According to an embodiment, a topical composition of the presentinvention in the form of a gel (see composition L in Table 2),comprises: (i) about 25% (w/w) trimethylsiloxysilicate, (ii) about 43%(w/w) methylsiloxane, (iii) about 4% (w/w) Cetyl PEG/PPG-10/1Dimethicone, (iv) about 1.5% (w/w) Tween 80, (v) about 25% (w/w) water,(vi) about 1% (w/w) pramoxine hydrochloride, (vii) about 0.25% (w/w)phenylephrine hydrochloride, and (viii) about 0.6% (w/w)Hydroxyethylcellulose (Natrosol HHX).

According to an embodiment, a topical composition of the presentinvention (see composition H1 in Table 1, Example 1 in the form of anoil-in-water emulsion liquid) comprises: (i) about 25% (w/w)trimethylsiloxysilicate, (ii) about 38% (w/w) methylsiloxane (0.54 cP),(iii) about 4% (w/w) Cetyl PEG/PPG-10/1 Dimethicone, (iv) about 3% (w/w)Tween 80, (v) about 30% (w/w) acetate buffer pH 4.4, (vi) about 1% (w/w)pramoxine HCl, and (vii) about 0.25% (w/w) phenylephrine HCl.

According to an embodiment, a topical composition of the presentinvention (see composition H2 in Table 1, Example 1 in the form of anoil-in-water emulsion liquid) comprises: (i) about 15% (w/w)trimethylsiloxysilicate, (ii) about 47% (w/w) methylsiloxane (0.54 cP),(iii) about 4% (w/w) Cetyl PEG/PPG-10/1 Dimethicone, (iv) about 3% (w/w)Tween 80, (v) about 20% (w/w) acetate buffer pH 4.4, (vi) about 1% (w/w)pramoxine HCl, (vii) about 0.25% (w/w) phenylephrine HCl, and (viii)about 0.01% (w/w) to about 0.1% (w/w) Pemulen TR-1.

Containers and Applicators

The compositions for use in the present invention are generally storedin a container-applicator device for use in a single dose application(e.g., a wipe or a swab in a disposable container) or for use inrepeated applications to the anus and rectum. Single dose applicatorsinclude those having breakable or removable seals that prevent moisture,including atmospheric moisture, from contacting the formulation.

In an embodiment of the invention, a topical water-based composition isin the form of a pre-packaged towelette/wipe. The wipe substrate istypically uniformly impregnated with the topical water-basedcomposition. According to an embodiment, the topical water-basedcomposition is in a liquid form, when applied to the wipe. According toan embodiment, the topical water-based composition is in a gel form,when applied to a wipe. The wipe provides the user with a single dose ofsterile medication. The topical composition is transferred to the bodysurface upon contacting the wipe with the target surface.

The design of wipes is well known to those of skill in the art. Eachwipe is generally packaged as a single-use sealed unit. The wipe isformed of woven or non-woven fabric, cloth or tissue substrate and theimpregnated wipe may be sealed into an enveloping sachet or pocket. Inan embodiment, the sachet or pocket is formed by sandwiching a foldedand impregnated wipe between two sheets of an aluminum foil/polyethylenefilm laminate. The sheets of laminate may comprise folded over portionsof a single sheet of such material.

A container-applicator may further comprise two parts: (1) a storagearea or reservoir which holds the composition and protects it from air,water and contaminants; and (2) the applicator which generally comprisesa specially shaped tip designed to aid in application of the compositionto the anorectal and/or genital area. In particular embodiments, theapplicator is an element integral to the container, for example, anelongated insertion tube extending from a reservoir. Alternately, thestorage area and the applicator may be separate components, such as atube reservoir and a separately supplied dropper. In yet otherembodiments, the container and the applicator may be supplied asseparate elements which are connected during use, for example viacompatible male and female connectors respectively provided on thecontainer and the applicator or vice versa.

For repeated and intermittent usage, minimal exposure to atmosphericmoisture is required. This can be achieved by devices having very narrowapplicator outlets and low initial dead space. One applicator for suchrepeated intermittent use may, for example, dispense the composition ina controlled drop wise manner, as described for example in U.S. Pat. No.4,958,748.

Still another container-applicator device comprises a brush or solidpaddle applicator wherein the topical composition is “painted” onto thesurface requiring treatment.

The container-applicator device for repeated and intermittent usage maycomprise a container suitable for non-sterile storage of thecomposition, and an applicator suitable for metered dispensing of thecomposition after opening of the applicator. In particular embodiments,the applicator is characterized as having a resealable opening of nomore than about 0.05 square inch (0.323 square centimeters) so as topermit the metered dispersement of the composition from the applicatorand which is capable of multiple administrations of the composition, andis further characterized as having resealing means such as a cap whicheither tightly mates with the applicator or which screws onto theapplicator. The opening may be at the terminus of an elongated andtapered tube-like member suitable for insertion into the anal canal andaccessing internal hemorrhoids. Suitable openings of the applicator areabout 0.001 to about 0.01 square inch (about 0.00645 to about 0.0645square centimeters).

In an embodiment, the walls of the container-applicator device are madeof a pliable material, so that upon application of pressure onto thewalls, the walls depress sufficiently to force the composition in thecontainer into the applicator and through the opening. In anotherembodiment, the composition is released from the applicator by gravityfeed methods well known in the art. Such methods do not requireapplication of pressure to the walls of the container.

In an embodiment, the applicator is manufactured with its openingcovered by a metal foil or other similar construction which closes thisopening until the device is ready for use. The opening is thenreinstated by use of a pin or similar device which punctures thecovering.

Such devices for intermittent use enable multiple uses of the topicalcomposition at different points in time by the same individual.

In container-applicator devices suitable for repeated intermittent uses,the topical composition is stored at ambient conditions and is selectedto be bacteriostatic (see, for example, U.S. Pat. No. 3,527,224). Whenthe selected composition is bacteriostatic, prolonged storage at ambientconditions can be achieved without regard to the sterility of theformulation because there is no adverse buildup of bacteria duringstorage.

The reservoir of the container-applicator device may be both air-tightand water-tight, and keeps the media within free from contaminants. Thereservoir may contain a desiccant material to keep the media free ofwater. Reservoirs may be of any shape, although shapes which provide fora smooth internal flow of media, such as cylindrical or conical shapes,are typically suitable. The size of the reservoir may vary within a widerange, but is typically slightly larger than the volume of compositionwhich will be placed inside the reservoir to minimize the amount of gaswithin the reservoir. The reservoir may be made from any of a variety ofmedical grade materials, such as plastics, excluding glass.Pharmaceutical agents of the topical composition suffer from caking whenstored in glass reservoir. The reservoir may be rigid, collapsible, orcompressible. Use of a compressible or collapsible reservoir allows theuser to have greater control over the rate at which the composition isexpressed, as exertion of pressure on a compressible or collapsiblereservoir would place a force on the on the composition causing it toflow at a faster rate than it would in the absence of such pressure. Thecompressible or collapsible reservoir design is especially suitable forthe topical composition in the form of gel, for which the force ofgravity may not be strong enough to cause a flow through an applicatorsufficient to treat hemorrhoids or fissures. Collapsible reservoirswhich retain their collapsed shape have the additional advantage ofreducing the amount of air which enters the reservoir following use.This advantage of collapsible containers is of greater importance inmultiple-use (reusable) devices, wherein media is typically keptrelatively free of potential contaminants between uses.

Applicator tips can be of any of a number of shapes, sizes, andconfigurations. They may be fairly rigid and may be made out of anymaterial which is compatible with the media formulation, for exampleplastic, excluding glass. The choice of a proper applicator tip for agiven application will depend on factors such as the viscosity of thecomposition, the desired application rate of the composition, the natureof the anorectal or genital disorder, and its severity.

The container-applicators of the present invention may be eithersingle-use or multiple-use devices. A container or reservoir containingenough topical composition for multiple applications may be configuredto accommodate replaceable tips. In such an embodiment, at the placewhereon the replaceable tips connect with the reservoir, the reservoirwould typically have a means such as a valve, septum or sealing gasketwhich allows the reservoir to be sealed in the absence of an applicatortip. Placing an applicator tip on the reservoir would cause the valve toopen, allowing composition to flow out from the reservoir. In thismanner, one reservoir containing enough composition for severalapplications could be used over a period of hours, days or weeks. Thisembodiment would also allow the user to use one reservoir withapplicator tips of varying shapes and sizes chosen to best accommodatethe anorectal or genital disorder during the healing process.

Uses

Disorders of the anorectal or genital region are commonly encounteredamong the general population, but are often inadequately unaddressed,since many patients delay or fail to seek medical attention due toembarrassment. Furthermore, many medications for such conditions fail toprovide adequate relief and healing. In addition, many medications whichare intended for treatment of conditions such as hemorrhoids, herpes,genital warts, anal warts may be difficult to self-administer, and areunsatisfactory due to their uncomfortable sensation after application.

The present invention provides compositions which are useful foreffectively treating a variety of anorectal disorders includinghemorrhoids, anal fissures, anal cracks, anal fistulas, anal abscesses,and anal pruritus, wherein the compositions provide enhanced therapeuticefficacy and are associated with improved patient compliance, ascompared to prior art compositions. The provided compositions may beuseful for simultaneously treating a number of anorectal disorders.

Hemorrhoids (also known as piles) form part of the normal human anatomyof the anal canal, but may become pathological when swollen or inflamed.In their physiological state they act as cushions composed ofarterio-venous channels and connective tissue that aid the passage ofstool. The symptoms of pathological hemorrhoids include rectal bleeding,tenderness and pain in the anorectal area.

Pathological hemorrhoids are typically classified as external orinternal, which are differentiated via their position with respect tothe dentate line. External hemorrhoids occur outside the anal verge (thedistal end of the anal canal) as varicosities of the veins draining theterritory of the inferior rectal arteries, which are branches of theinternal pudendal artery. External hemorrhoids are frequently painful,and are often accompanied by swelling, skin irritation and itching.External hemorrhoids are prone to thrombosis, which may occur if thevein ruptures and/or a blood clot develops.

Internal hemorrhoids occur within the rectum as varicosities of veinsdraining the territory of branches of the superior rectal arteries. Asthis area lacks pain receptors, internal hemorrhoids are often painlessand affected individuals may be unaware of their occurrence. Internalhemorrhoids may however, bleed when irritated. Untreated internalhemorrhoids can lead to the more sever conditions of prolapsed orstrangulated hemorrhoids. Prolapsed hemorrhoids are severely distendedsuch that they are extruded outside the anus. If the anal sphinctermuscle goes into spasm and traps a prolapsed hemorrhoid outside the analopening, the supply of blood is cut off, and the hemorrhoid becomes astrangulated hemorrhoid.

Internal hemorrhoids can be further graded by the degree of prolapse, inwhich Grade I is characterized by the absence of prolapse; Grade II ischaracterized by prolapse upon defecation but which reducespontaneously; Grade III is characterized by prolapse upon defecation,which may be manually reduced; and Grade IV is characterized by prolapsewhich cannot be manually reduced.

An anal fissure is a crack or tear in the skin of the anal canal. Acutecases may be associated with severe periodic pain after defecation,while chronic cases are associated with less intense pain. Anal fissuresusually extend from the anal opening and are usually located posteriorlyin the midline. Fissure depth may be superficial or extend down to theunderlying sphincter muscle. Most anal fissures are due to stretching ofthe anal mucosa beyond their capability. A common cause of non-healingchronic fissures is spasm of the internal anal sphincter muscle,resulting in impaired blood supply to the anal mucosa. The result is anon-healing ulcer, which may become infected by fecal bacteria.

Non-surgical conventional treatments for acute and chronic anal fissuresare generally those used for hemorrhoids. Topically applied medicationsused for relaxation of the sphincter muscle include nitroglycerine,nifedipine, diltiazem, verapamil, sildenafil citrate, and/or lidocaine.Surgical treatment procedures such as anal stretch (Lord's operation) orlateral sphincterotomy are aimed to decrease sphincter spasm. Anotherapproach involves injection of botulinum toxin into the anal sphincter.

Anorectal or perianal abscess (also known as anal/rectal abscess,perianal/perirectal abscess) is an abscess occurring adjacent to theanus, due to infection at one of the anal crypts of Morgagni. Most casesare sporadic, although individuals with diabetes mellitus or Crohn'sdisease, or those undergoing chronic steroid treatment have increasedrisk and incidence. The condition is generally treated by surgery todrain the infection, followed by oral administration of antibiotics andpossibly topical treatments. Anal abscess often leads to an analfistula, which is the development of an infected channel within a glandbetween the anal canal and external skin near the anus or rectum. Thiscondition also requires surgical treatment generally followed byadministration of antibiotics.

Anal pruritus (also known as pruritus ani or anusitis) is an irritationof the skin at the anus, associated with intensive urge to scratch theaffected area. The condition may be idiopathic, or associated withvarious factors or co-existing conditions, including occult or overtfecal soiling, ingestion of certain foods, bacterial or fungalinfection, hemorrhoids or additional co-existing anorectal disorders,and dermatological conditions, in particular allergic contact dermatitisor psoriasis. Treatment measures include enhanced hygiene, antibioticsor antifungal medications when infections are present, various creamsand ointments, generally containing local anesthetics, vasoconstrictors,protectants or combinations thereof, and topical steroids. Thecomposition is applied to areas of the anal canal or rectum affected byhemorrhoids, fissures, fistulae, cracks, warts or pruritus, underconditions suitable for film formation of the composition so as to forma protective coating and typically under non-sterile conditions. Ingeneral, sufficient amounts of topical composition are employed to coverthe entire affected mucosal surface area. In an embodiment, the coatingis extended by at least about 1 centimeter and by at least about 5centimeters beyond the affected surface area.

The term “therapeutically effective amount” as used herein means anamount of the pharmaceutical agent which is sufficient to provide abeneficial effect to the subject to which the pharmaceutical agent isadministered. More specifically, a therapeutically effective amountmeans an amount of the pharmaceutical agent effective to alleviate orameliorate the symptoms of an anorectal or genital disorder of thesubject being treated.

As the anorectal or genital disorders are treated with compositions ofcertain fixed concentrations, reference is made herein to“therapeutically effective concentration”.

After an initial layer of topical composition has been applied and thesolvent has evaporated, providing an initial dried film coating, asecond layer may be applied over the initial film. Additional amounts oftopical composition can be applied as needed.

In an embodiment, a topical composition is employed to form a coating ofless than about 0.5 mm thick. In an embodiment, a topical composition isemployed to form a coating of at least about 0.1 mm thick. Such coatingscan be formed by applying, for example, about 0.02 ml of topicalcomposition per square centimeter of affected surface area.

In general, the particular length of time required for film formationwill vary depending on factors such as the amount of compositionapplied, the temperature of the rectal or anal mucosal area, themoisture content of the rectal or anal, the surface area for compositionapplication, and the like. However, in an embodiment, film formation isgenerally complete within about 10 to about 60 seconds. During thisperiod, the person to whom application of the topical composition hasbeen made may minimize actions and body movements thus allowing thecomposition to form a dried film coating.

The topical compositions of the present invention typically act attemperatures between room temperature (20° C.) and body temperature (37°C.). The dried films are conformable and comfortable and may be elasticand flexible, and do not irritate the skin and mucous membrane duringthe application and in use after drying. The dried films are typicallysubstantially painless and easily removable substantially without pain.The dried films formed from the topical compositions are also typicallysubstantially non-water sensitive and waterproof. The dried films formedfrom the topical compositions comprise finely-dispersed pharmaceuticalingredients, which can be gradually released to the adhesion area.

The compositions of the present invention are applicable to both humanpatients and to non-human mammalian subjects such as in veterinary use,for example for treatment of canine, feline, equine, bovine, porcine andprimate species.

The foregoing description of the specific embodiments will so fullyreveal the general nature of the invention that others can, by applyingcurrent knowledge, readily modify and/or adapt for various applicationssuch specific embodiments without undue experimentation and withoutdeparting from the generic concept, and, therefore, such adaptations andmodifications should and are intended to be comprehended within themeaning and range of equivalents of the disclosed embodiments. It is tobe understood that the phraseology or terminology employed herein is forthe purpose of description and not of limitation. The means, materials,and steps for carrying out various disclosed functions may take avariety of alternative forms without departing from the invention.

The following examples illustrate certain embodiments of the inventionbut are not meant to limit the scope of the claims in any way. Thefollowing examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how tomake and use the described invention, and are not intended to limit thescope of what the inventors regard as their invention nor are theyintended to represent that the experiments below are all or the onlyexperiments performed. Efforts have been made to ensure accuracy withrespect to numbers used (e.g. amounts, temperature, etc.) but someexperimental errors and deviations should be accounted for. Unlessindicated otherwise, parts are parts by weight, molecular weight isweight average molecular weight, temperature is in degrees Centigrade,and pressure is at or near atmospheric.

Example 1

Table 1 summarizes various embodiments of topical compositions of thepresent invention in the form of an oil-in-water emulsion liquidprepared for use in treating hemorrhoids.

TABLE 1 g per 100 g product Ingredient A B C D E F G H H1 H2Trimethylsiloxysilicate 15 15 15 15 20 20 13 15 25 25Hexamethyldisiloxane 22 22 22 22 24 26 18 43 Isooctane 21 21 21 22.5 2020 17 Methylsiloxane 38.25 46.74 (0.65 cP) Cetyl PEG/PPG- 4 4 4 4 4 4 44 10/1 Dimethicone Tween 80 1.5 1.5 1.5 1.5 1.5 3 Tween 20 2 SodiumLauryl 1.5 3 3 Sulfate Water 25 24.5 25 25 30 30 35 25 Acetate Buffer 3020 pH 4.4 Pramoxine HCl 1 1 1 1 1 1 1 1 1 1 Phenylephrine 0.25 0.25 0.250.25 0.25 0.25 0.25 0.25 0.25 0.25 HCl Bis- 5 5 5 5 5 5 vinyldimethiconeVinyldimethicone 5 5 5 5 5 5 and hydrogen dimethicone Cyclopentasiloxane1 1 1 1 1 1 and dimethicone blend Pemulen TR-1 0.01

Example 2

Composition H1 of Example 1 was prepared as follows:

Trimethylsiloxysilicate powder was dissolved in methylsiloxane at roomtemperature. Cetyl PEG/PPG-10/1 Dimethicone was added to solution oftrimethylsiloxysilicate. Pramoxine and phenylephrine were dissolved inwater. The pH of the aqueous solution was adjusted to 4.2-4.4 by acetatebuffer. Tween 80 was added to the aqueous solution. Thetrimethylsiloxysilicate solution was combined with the aqueous solutionand mixed by means of a homogenizer at room temperature.

The obtained topical liquid solution was applied to a wipe substrate andsealed to provide a sealed package of single-use wipe impregnated withthe topical liquid composition. The composition is applied using singleuse wipe, wiping the anal region of an adult subject suffering fromexternal hemorrhoids.

Example 3

Table 2 summarizes various embodiments of topical compositions of thepresent invention in the form of a gel for treatment of hemorrhoids.

TABLE 2 g per 100 g product Ingredient I J K L Trimethylsiloxysilicate15 17 20 25 Hexamethyldisiloxane 18 18 21 Methylsiloxane (0.65 cP) 42.65Isooctane 19 20 22 Cetyl PEG/PPG-10/1 4 4 4 Dimethicone Tween 80 1.5 1.51.5 Sodium Lauryl Sulfate 3 Water 30 30 30 25 Pramoxine HCl 1 1 1 1Phenylephrine HCl 0.25 0.25 0.25 0.25 Bis-vinyldimethicone 5 5Vinyldimethicone and 5 5 hydrogen dimethicone Cyclopentasiloxane and 1 1dimethicone blend Hydroxypropyl 0.5 0.5 0.5 methylcelluloseHydroxyethylcellulose 0.6 (Natrosol HHX)

Example 4

Composition L was prepared as follows:

Trimethylsiloxysilicate powder was dissolved at RT in methylsiloxane.Silicon Surfactant Cetyl PEG/PPG-10/1 Dimethicone was added to asolution of Trimethylsiloxysilicate. Pramoxine and phenylephrine weredissolved in water. The pH of the aqueous solution was adjusted to4.2-4.4 by an acetate buffer. Tween 80 was added to the aqueous solutionwith slow mixing to avoid bubbling. Hydroxyethylcellulose (Natrosol HHX)was dispersed in the aqueous phase under intensive mixing and heating upto 70 deg C. After the mixture was formed, the mixing was continueduntil it cooled to room temperature. The trimethylsiloxysilicatesolution was combined with the aqueous solution and mixed in ahomogenizer at room temperature. Upon dissolution of hydroxypropylmethylcellulose in the aqueous phase, whereupon a viscous gel wasformed.

The viscous topical gel composition obtained had a viscosity rangingfrom 25000-45000 cP.

Example 5

A female patient aged 42 applied the gel composition L of Table 2,Example 3 on the elbow, neck and internal part of the arm. Shortlythereafter (about 20 seconds) the composition dried and left a thin filmon the skin.

The films were examined after 12, 18 and 24 hrs for durability andflexibility. During this period the patient carried out their usualdaily activities and took one shower.

It was found that the films were durable and remained intact after 12,18 and 24 hrs. The films did not fall off the body surface and did notcrack or flake off. It was found that the films remained flexible after12, 18 and 24 hrs. The films closely followed the patient's skinirregularities as well as skin movement throughout the day during normalactivity. The skin under the film was slightly pale, which shows thevasoconstrictor phenylephrine was still active after 24 hrs. After 24hrs, the film was removed from the skin and tested by high performanceliquid chromatography (HPLC), whereupon significant amounts of the twoactives (pramoxine and phenylephrine) were found in the film despite theextended period of time.

Example 6 (Prophetic)—Durability of Films Obtained on Drying of theCompositions of the Present Disclosure

A test will be conducted to assess durability of dried films of thepresent disclosure. The model will be based on the principle thatefficacious films provide a physical barrier between the skin and theexternal environment. Therefore, the film should also prevent wash-offand wear-off of a harmless inert marker substance. Activated carbonpowder (ACP) is one such marker.

Film performance will be assessed by randomly applying films of thepresent disclosure over uniformly made ACP prepared sites on the backsof healthy adult subjects, and measuring the amount of ACP remaining onthose sites over a wear period (e.g., one-day period, two-day period,three-day period or more). Subjects will go about normal dailyactivities and will be asked to shower once per day and avoid excessivephysical activity or prolonged water exposure. On a daily basis,standardized digital photographs will be taken of the test sites andused to monitor the amount of ACP remaining using computer-assistedimage analysis. The amount of marker stain (ACP) remaining after 1, 2,and 3 days of wear will be used as a measure of film effectiveness. Themore stain remaining, the more effective the film at protecting the testsite. The results can be presented as a chart of mean±SEM durabilityexpresses as a percentage of the original ACP marker on Day 0.

Example 7 (Prophetic)—Flexibility of Films Obtained on Drying of theCompositions of the Present Disclosure

A test will be conducted to assess flexibility of dried films of thepresent disclosure. The films will be prepared on synthetic skin andbent over three sized mandrel bend rods (½″, ¼″, ⅛″) based on ASTMmethod D4338-97. Multiple data points will be collected for each film.Whether or not the film cracked during the bending process will berecorded.

A tattoo practice skin (synthetic skin) coated with a film of thepresent disclosure. The skin will be folded to form an inverted U-shapedangle over the mandrel maintaining intimate contact with the uppersurface of the film. Using a fresh specimen for each test, the test willbe repeated with progressively smaller diameter mandrels.

Procedure:

-   -   1) Film will be applied onto tattoo practice skin with a        dimension of 2×4 inches.    -   2) The test films and the test apparatus will be stored at the        test conditions for 24 hours.    -   3) The tests will be run in the same environment used to        condition the test films and test apparatus.    -   4) The largest diameter mandrel will be positioned in the        horizontal operating position in the test frame.    -   5) The test film will be grasped between the thumb and        forefinger of one hand, with the longest dimensions between the        fingers. For low-temperature testing, a cotton work glove can be        used to insulate the test film from the warm fingers.    -   6) A flat steel (or other support structure) of the test film        will be laid tangentially at right angles to the longitudinal        axis of the test mandrel.    -   7) The test film will be folded with the lower surface opposite        to the mandrel to form an inverted U-shaped angle over the        mandrel maintaining intimate contact with the mandrel.    -   8) Any fracture, crazing, or cracking of the film, observed with        the naked eye, will be recorded.    -   9) A fresh film will be folded onto the next smaller diameter        mandrel.    -   10) The test will be repeated a number of times, using fresh        films, on three mandrels with different diameters.    -   11) Flexibility of the films will be determined by the ability        of the films to not crack when subjected to bending.

Example 8—Efficacy of Compositions of the Present Invention in theTreatment of Hemorrhoids

Background:

In a randomized clinical study, patients were divided into 3 groups andreceived either PP-110 gel (composition L in Table 2), PP-110 wipes(composition H1 in Table 1) or Preparation-H® cream as a comparator.PP-110 was applied once daily, while Preparation-H was applied 4 times aday, as indicated.

All patients were asked to record parameters such as pain, bleeding,itching, swelling, discomfort, and mucus discharge over a period of 14days while using the assigned treatment. For most parameters, patientswere asked to choose between 0=none, 1=mild, 2=moderate and3=significant for each day. The only exception was pain, where they wereasked to select a pain level between 1=none to 10=maximal.

Results:

Based on the first 32 patients who completed the protocol (9 of themwith PP-110 gel, 11 with PP-110 wipes, and 12 with Preparation-H cream),the following interim results were obtained:

Pain:

Reported pain, throughout the 14 days of treatment for PP-110 (gel orwipes) was reduced compared to reported pain in the Preparation-H arm,even though PP-110 was used once daily and Preparation-H was used 4times per day. FIG. 1 shows hemorrhoidal pain level after treatment withcompositions of the present invention as gel and wipes, as compared toPreparation H. The data presented are the delta meaning the change fromthe previous day for each parameter measured.

Itching:

Itching, throughout the 14 days of treatment for PP-110 (gel or wipes)was significantly reduced compared to reported itching in thePreparation-H arm. FIG. 2 shows hemorrhoidal itching after treatmentwith compositions of the present invention as gel and wipes as comparedto Preparation H. The data presented are the delta meaning the changefrom the previous day for each parameter measured.

Swelling:

For swelling values for the PP-110 gel and wipe arms throughout the 14days of treatment were significantly reduced compared to reportedswelling in the Preparation-H arm. FIG. 3 shows hemorrhoidal swellingafter treatment with compositions of the present invention as gel andwipes, as compared to Preparation H. The data presented are the deltameaning the change from the previous day for each parameter measured.

Bleeding:

PP-110 gel patients and Preparation-H patients showed similar bleedingresults throughout the 14 days. PP-110 wipe patients were slightlybehind in the first 7 days of treatment, but caught on after that. FIG.4 shows hemorrhoidal bleeding after treatment with compositions of thepresent invention as gel and wipes, as compared to Preparation H. Thedata presented are the delta meaning the change from the previous dayfor each parameter measured.

Discomfort:

Results of all 3 arms with respect to discomfort were comparable, eventhough PP-110 patients used the product once daily and Preparation-Hpatients—4 times a day. FIG. 5 shows hemorrhoidal discomfort aftertreatment with compositions of the present invention as gel and wipes,as compared to Preparation H.

Summary:

In all clinical parameters one or both of PP-110 arms showed comparableor superior results compared to the Preparation-H arm. This includespain, itching, swelling, bleeding and discomfort, and was achieved eventhough PP-110 was applied once daily and Preparation-H was applied 4times per day. The data presented are the delta meaning the change fromthe previous day for each parameter measured.

Example 9—Liquid Compositions with Pemulen TR-1 for the Preparation ofWipes

Composition H2 of Table 1 in Example 1 was prepared similarly tocomposition H1, with added Pemulen TR-1:

Trimethylsiloxysilicate powder was dissolved in methylsiloxane at roomtemperature. Cetyl PEG/PPG-10/1 Dimethicone was added to solution oftrimethylsiloxy silicate. Pramoxine and phenylephrine were dissolved inwater. The pH of the aqueous solution was adjusted to 4.2-4.4 by acetatebuffer. Tween 80 was added to the aqueous solution. Thetrimethylsiloxysilicate solution was combined with the aqueous solutionand mixed by means of a homogenizer at room temperature.

A topical liquid composition was obtained, whose viscosity ranges from1-1.2 cP, close to the viscosity of water.

The obtained topical liquid composition was applied to a wipe substrateand sealed to provide a sealed package of single-use wipe impregnatedwith the topical liquid composition. The composition is applied usingsingle use wipe, wiping the anal region of an adult subject sufferingfrom external hemorrhoids.

All patents, patent applications, and published references cited hereinare hereby incorporated by reference in their entirety. It will beappreciated that several of the above-disclosed and other features andfunctions, or alternatives thereof, may be desirably combined into manyother different systems or application. Various presently unforeseen orunanticipated alternatives, modifications, variations, or improvementstherein may be subsequently made by those skilled in the art.

What is claimed is:
 1. A method of treating an anorectal or genitaldisorder comprising: topically applying to the anorectal or genitalsurface of a subject in need of such treatment a therapeuticallyeffective amount of a topical anorectal or genital compositioncomprising: from 10.0% (w/w) to 30.0% (w/w) of trimethylsiloxysilicate;from 1.0% (w/w) to 5.0% (w/w) of at least one surfactant; from 30.0%(w/w) to 75.0% (w/w) of at least one non-polar volatile siloxanesolvent; from about 15% (w/w) to about 40% (w/w) of water; and atherapeutically effective concentration of at least one pharmaceuticalagent, selected from the group consisting of pramoxine, phenylephrine,hydrocortisone, salicylic acid, nitroglycerine, sildenafil, nifedipine,diltiazem, verapamil, procaine, lidocaine, tetracaine, dibucaine,prilocaine, phenacaine, benzyl alcohol, benzocaine, diperodon,dyclonine, dimethisoquin, epinephrine, tetrahydrozoline hydrochloride,an amphetamine, an antihistamine, methylphenidate, mephedrone,oxymetazoline, pseudoephedrine, psilocybin, ephedrine sulphate,imiquimod, podophyllin, podophylotoxin, trichloroacetic acid,bichloroacetic acid, formic acid, fluorouracil, sinecatechins, plantextracts, acyclovir, penciclovir, famciclovir, docosanol or their saltsand combinations thereof, wherein the composition is sufficientlydesigned to dry within 60 seconds after application to the anorectal orgenital surface to form a dried composition, and wherein the driedcomposition forms: (i) a flexible film, wherein the flexible filmclosely follows irregularities of the surface as well as movement of thesurface, and (ii) a durable film, wherein the durable film does notcrack or flake off and remains intact for more than 12 hours givingrelease of the pharmaceutical agent for an extended period of time. 2.The method of claim 1, comprising topically applying twice weekly to theanorectal or genital surface of the subject in need of such treatmentthe therapeutically effective concentration of the composition.
 3. Themethod of claim 1, comprising topically applying once daily to theanorectal or genital surface of the subject in need of such treatmentthe therapeutically effective concentration of the composition.
 4. Themethod of claim 1, wherein, after a period of time post topicalapplication of the composition, a similar or better therapeutic effectis observable than a commercially available composition comprising thesame active ingredient(s) in the same concentrations wherein appliedseveral times daily.
 5. The method of claim 1, wherein the genitaldisorder is genital warts or herpes.
 6. The method of claim 1, whereinthe anorectal disorder is anal warts or herpes.
 7. The method of claim1, wherein the anorectal disorder is selected from the group consistingof hemorrhoid anal fissures, anal cracks, anal fistulas, anal abscessesand anal pruritus.
 8. The method of claim 1, wherein the composition isin the form of a gel.
 9. The method of claim 1, wherein the compositionis in the form of an oil-in-water emulsion.
 10. The method of claim 1,wherein in the composition, the at least one surfactant is apolysorbate.
 11. The method of claim 1, wherein in the composition, theat least one non-polar volatile siloxane solvent is selected from thegroup consisting of methylsiloxane, hexamethyldisiloxane, andcombinations thereof.
 12. The method of claim 1, wherein the compositionfurther comprises an additive selected from the group consisting of adimethicone/vinyl dimethicone crosspolymer, a silicone gum blend, agelling agent, and a combination thereof.
 13. The method of claim 1,wherein the composition further comprises a buffer to adjust the pH ofthe composition to a pH of about 4.2-4.4.
 14. The method of claim 1,wherein the composition further comprises an organosilicone surfactant.15. The method of claim 1, wherein the composition further comprises aviscosity modifier.
 16. The method of claim 1, wherein the compositioncomprises: about 25.0% (w/w) of trimethylsiloxysilicate; from about 1.0%(w/w) to about 5.0% (w/w) of polyoxyethylene sorbitan monooleate; andfrom about 30.0% (w/w) to about 50.0% (w/w) of a non-polar volatilesiloxane solvent.
 17. The method of claim 1, wherein the genital oranorectal disorder is anal or genital warts and wherein the compositioncomprises 4.0% (w/w) to 5.0% (w/w) imiquimod.
 18. The method of claim 1,wherein the genital or anorectal disorder is anal or genital warts andwherein the composition comprises 0.5% (w/w) podophyllotoxin.
 19. Themethod of claim 1, wherein the genital or anorectal disorder is anal orgenital warts and wherein the composition comprises 1.0% (w/w) to 20%(w/w) salicylic acid, 0.1% (w/w) to 10% (w/w) 5-fluorouracil or acombination thereof.
 20. The method of claim 1, wherein the genital oranorectal disorder is anal or genital herpes and wherein the compositioncomprises an antiviral selected from the group consisting of acyclovir,penciclovir, famciclovir, docosanol and combinations thereof.